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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">1368274</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2024.1368274</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Systematic Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Associated factors with voriconazole plasma concentration: a systematic review and meta-analysis</article-title>
<alt-title alt-title-type="left-running-head">Li et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2024.1368274">10.3389/fphar.2024.1368274</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Li</surname>
<given-names>Xiaoqi</given-names>
</name>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2625196/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Hu</surname>
<given-names>Qiaozhi</given-names>
</name>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Xu</surname>
<given-names>Ting</given-names>
</name>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1332537/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
</contrib-group>
<aff>
<institution>Department of Pharmacy</institution>, <institution>West China Hospital</institution>, <institution>Sichuan University</institution>, <addr-line>Chengdu</addr-line>, <addr-line>Sichuan</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/19959/overview">Anick B&#xe9;rard</ext-link>, Montreal University, Canada</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1507077/overview">Irene Garc&#xed;a Garc&#xed;a</ext-link>, University Hospital La Paz, Spain</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1310830/overview">Katarzyna Kosicka-Noworzy&#x144;</ext-link>, Poznan University of Medical Sciences, Poland</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Ting Xu, <email>tingx2009@163.com</email>
</corresp>
<fn fn-type="equal" id="fn001">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors share first authorship</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>23</day>
<month>08</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1368274</elocation-id>
<history>
<date date-type="received">
<day>10</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>12</day>
<month>08</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Li, Hu and Xu.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Li, Hu and Xu</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>
<bold>Background:</bold> Voriconazole plasma concentration exhibits significant variability and maintaining it within the therapeutic range is the key to enhancing its efficacy. We conducted a systematic review and meta-analysis to estimate the prevalence of patients achieving the therapeutic range of plasma voriconazole concentration and identify associated factors.</p>
<p>
<bold>Methods:</bold> Eligible studies were identified through the PubMed, Embase, Cochrane Library, and Web of Science databases from their inception until 18 November 2023. We conducted a meta-analysis using a random-effects model to determine the prevalence of patients who reached the therapeutic plasma voriconazole concentration range. Factors associated with plasma voriconazole concentration were summarized from the included studies.</p>
<p>
<bold>Results:</bold> Of the 60 eligible studies, 52 reported the prevalence of patients reaching the therapeutic range, while 20 performed multiple linear regression analyses. The pooled prevalence who achieved the therapeutic range was 56% (95% CI: 50%&#x2013;63%) in studies without dose adjustment patients. The pooled prevalence of adult patients was 61% (95% CI: 56%&#x2013;65%), and the pooled prevalence of children patients was 55% (95% CI: 50%&#x2013;60%) The study identified, in the children population, several factors associated with plasma voriconazole concentration, including age (coefficient 0.08, 95% CI: 0.01 to 0.14), albumin (&#x2212;0.05 95% CI: &#x2212;0.09 to &#x2212;0.01), in the adult population, some factors related to voriconazole plasma concentration, including omeprazole (1.37, 95% CI 0.82 to 1.92), pantoprazole (1.11, 95% CI: 0.17&#x2013;2.04), methylprednisolone (&#x2212;1.75, 95% CI: &#x2212;2.21 to &#x2212;1.30), and dexamethasone (&#x2212;1.45, 95% CI: &#x2212;2.07 to &#x2212;0.83).</p>
<p>
<bold>Conclusion:</bold> The analysis revealed that only approximately half of the patients reached the plasma voriconazole concentration therapeutic range without dose adjustments and the pooled prevalence of adult patients reaching the therapeutic range is higher than that of children. Therapeutic drug monitoring is crucial in the administration of voriconazole, especially in the children population. Particular attention may be paid to age, albumin levels in children, and the use of omeprazole, pantoprazole, dexamethasone and methylprednisolone in adults.</p>
<p>
<bold>Systematic Review Registration:</bold> <ext-link ext-link-type="uri" xlink:href="https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023483728">https://www.crd.york.ac.uk/prospero/display_record.php?ID&#x3d;CRD42023483728</ext-link>.</p>
</abstract>
<kwd-group>
<kwd>voriconazole</kwd>
<kwd>drug monitoring</kwd>
<kwd>voriconazole plasma concentration</kwd>
<kwd>factors</kwd>
<kwd>meta-analysis</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Pharmacoepidemiology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>The issue of invasive fungal infections is significant in contemporary medicine, notably impacting human health, especially among patients with compromised immune systems, resulting in increased morbidity and mortality (<xref ref-type="bibr" rid="B41">Hope et al., 2013</xref>). Voriconazole, a second-generation triazole, demonstrates broad-spectrum antifungal activity against <italic>Candida</italic>, C. neoformans, Aspergillus, various dimorphic fungi, and other medically significant fungi (<xref ref-type="bibr" rid="B83">Sabatelli et al., 2006</xref>). As an azole antifungal agent, it is prescribed for treating and preventing invasive fungal infections, particularly invasive aspergillosis (<xref ref-type="bibr" rid="B96">Tissot et al., 2017</xref>; <xref ref-type="bibr" rid="B101">Walsh et al., 2008</xref>; <xref ref-type="bibr" rid="B76">Patterson et al., 2016</xref>).</p>
<p>Voriconazole demonstrates linear pharmacokinetics in children, whereas its pharmacokinetics are nonlinear in adults (<xref ref-type="bibr" rid="B20">Chen X. et al., 2022</xref>; <xref ref-type="bibr" rid="B94">Theuretzbacher et al., 2006</xref>). As the dosage increases, the clearance of the drug does not necessarily increase linearly, potentially being affected by saturation effects or other enzymatic activities (<xref ref-type="bibr" rid="B66">Ludden, 1991</xref>). This non-linearity renders the drug more complex and increases the challenge of adjusting dosages and predicting drug concentrations in clinical settings. In addition to its non-linear pharmacokinetics, drug interactions, CYP2C19 genotype, and liver function are potential influences on plasma levels of voriconazole. A correlation between voriconazole exposure and response has been confirmed (<xref ref-type="bibr" rid="B28">Dolton and Mclachlan, 2014</xref>). Low voriconazole concentration may elevate the risk of treatment failure, while higher concentrations correlate with heightened toxicity (<xref ref-type="bibr" rid="B34">Elewa et al., 2015</xref>). Consequently, maintaining an ideal voriconazole plasma concentration is important but difficult in both children and adults.</p>
<p>A randomized controlled trial indicated significantly better outcomes (complete or partial response) in patients receiving therapeutic drug monitoring (TDM) compared to those not receiving TDM (<xref ref-type="bibr" rid="B75">Park et al., 2012</xref>). Therefore, performing TDM on voriconazole is helpful in maintaining the ideal plasma concentration of voriconazole. For TDM of voriconazole, trough concentration is commonly measured (<xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>). The recommended therapeutic range of voriconazole plasma concentration varies in different regions. A meta-analysis suggested that maintaining the trough concentration of voriconazole between 0.5 and 3.0&#xa0;mg/L optimizes clinical efficacy while minimizing hepatotoxicity (<xref ref-type="bibr" rid="B49">Jin et al., 2016</xref>). Substantial studies indicated that voriconazole trough concentrations maintained above 1.0&#xa0;mg/L and below 4.0&#xa0;mg/L are effective and safe (<xref ref-type="bibr" rid="B37">Hamada et al., 2012</xref>; <xref ref-type="bibr" rid="B97">Troke et al., 2011</xref>; <xref ref-type="bibr" rid="B47">Jeans et al., 2012</xref>; <xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>). These studies (<xref ref-type="bibr" rid="B37">Hamada et al., 2012</xref>; <xref ref-type="bibr" rid="B97">Troke et al., 2011</xref>; <xref ref-type="bibr" rid="B47">Jeans et al., 2012</xref>; <xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>; <xref ref-type="bibr" rid="B75">Park et al., 2012</xref>; <xref ref-type="bibr" rid="B49">Jin et al., 2016</xref>), highlight that maintaining specific therapeutic ranges of plasma voriconazole concentration increases the likelihood of therapeutic success. Early TDM to achieve specific range contributes significantly to treatment success (<xref ref-type="bibr" rid="B79">Resztak et al., 2021</xref>).</p>
<p>Multiple factors have been confirmed to be associated with interindividual variability in voriconazole concentrations (e.g., CYP2C19 genotype), and several cross-sectional studies have investigated the prevalence of patients achieving therapeutic range and the factors associated with voriconazole plasma concentration. However, there are no evidence-based medical studies summarizing the prevalence of patients reaching the specific therapeutic range of plasma concentration the factors affecting the plasma concentration of voriconazole. Therefore, this systematic review and meta-analysis aggregated data to estimate the prevalence of patients achieving the therapeutic range of plasma voriconazole concentration. Additionally, it analyzed various factors influencing plasma voriconazole levels. The findings could assist clinicians in making more informed treatment decisions. With further research and the accumulation of medical evidence, clinicians can optimize voriconazole use to improve patient outcomes and survival rates.</p>
</sec>
<sec sec-type="methods" id="s2">
<title>2 Methods</title>
<p>This study was conducted according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (<xref ref-type="bibr" rid="B91">Stroup et al., 2000</xref>) and followed the Preferred Reporting Items for Systematics Reviews and Meta-Analyses guidelines (<xref ref-type="bibr" rid="B70">Moher et al., 2015</xref>). The protocol of this review was registered in PROSPERO (CRD42023483728).</p>
<sec id="s2-1">
<title>2.1 Search strategy</title>
<p>A preliminary scoping search was conducted in PubMed, the Cochrane Library, Web of Science, and Embase from their inception until 18 November 2023. The search strategy employed a combination of Medical Subject Headings (MeSH) terms and free-text terms. Detailed search strategies are shown in <xref ref-type="sec" rid="s11">Supplementary Table S1</xref>.</p>
</sec>
<sec id="s2-2">
<title>2.2 Selection criteria</title>
<p>Studies were eligible for inclusion if they: 1) involved patients undergoing voriconazole treatment; 2) reported the number of patients achieving therapeutic plasma concentrations of voriconazole or provided coefficients and standard errors from multiple linear regression analyses; 3) were published in English; and 4) utilized cross-sectional or cohort study designs. Exclusion criteria were 1) conference abstracts, reviews, letters, or commentaries; and 2) studies where data extraction was infeasible or if the independent variable in the multiple linear regression analysis was not clearly defined.</p>
</sec>
<sec id="s2-3">
<title>2.3 Study selection</title>
<p>Two reviewers (XQ Li and QZ Hu) independently screened the titles and abstracts of the preliminarily included studies, adhering to the predefined inclusion and exclusion criteria. In instances where a study&#x2019;s eligibility was unclear from the abstract alone, a comprehensive assessment of the full text was conducted. Any discrepancies during the screening process were resolved by consulting a third senior investigator (T Xu).</p>
</sec>
<sec id="s2-4">
<title>2.4 Data extraction</title>
<p>Data extraction from the included literature was independently conducted by two reviewers (XQ Li and QZ Hu). The following information was collected: author(s), publication year, country of study, study type, patient age and sex demographics, type of treatment settings, method of voriconazole measurement, duration of treatment, number of patients enrolled, number of blood samples analyzed, number of patients achieving the therapeutic range of plasma voriconazole concentration, the execution of multiple linear regression analyses, and, where applicable, coefficients and standard errors derived from these regressions.</p>
</sec>
<sec id="s2-5">
<title>2.5 Quality assessment</title>
<p>Two reviewers (XQ Li and QZ Hu) assessed the quality of the included studies using the Agency for Healthcare Research and Quality (AHRQ) criteria, which comprise 11 items. Each item was rated as &#x201c;yes,&#x201d; &#x201c;no,&#x201d; or &#x201c;unclear.&#x201d; A &#x201c;yes&#x201d; response earned 1 point, while a &#x201c;no&#x201d; or &#x201c;unclear&#x201d; received no points. Based on their total scores, the studies were categorized into three quality levels: 0&#x2013;3 indicated low quality, 4&#x2013;7 moderate quality, and 8&#x2013;11 high quality.</p>
</sec>
<sec id="s2-6">
<title>2.6 Statistical analysis</title>
<p>A meta-analysis was conducted to evaluate the prevalence of patients who achieved the therapeutic range of plasma voriconazole concentration, using STATA version 15. The pooled prevalence was reported proportionally, with 95% confidence intervals (CIs). Heterogeneity between studies was assessed using the &#x3c7;2 test and the I<sup>2</sup> statistic, with an I<sup>2</sup> value &#x3e;50% suggesting significant heterogeneity. Accordingly, the Der Simonian-Laird random-effects model was applied to analyze such cases. A sensitivity analysis was performed to ensure the robustness of the meta-analysis findings. The subgroup analysis was performed based on the study cohort (adults vs. children) and the method of dose adjustments. The potential for publication bias was evaluated using Egger&#x2019;s test, Begg&#x2019;s test, and the trim-and-fill method. Additionally, for instances where two or more studies with children or adults population reported coefficients and standard errors (SEs) from multiple linear regression analyses, we summarized these coefficients and SEs using a random-effects model, following the approach outlined by <xref ref-type="bibr" rid="B80">Rolden et al. (2014)</xref>.</p>
</sec>
</sec>
<sec sec-type="results" id="s3">
<title>3 Result</title>
<sec id="s3-1">
<title>3.1 Study selection</title>
<p>A comprehensive search across four databases yielded 3,292 literature references. Following the exclusion of 1,154 duplicates, 2,138 studies underwent title and abstract screening. Ultimately, 60 studies were selected for qualitative synthesis based on a full-text review (<xref ref-type="bibr" rid="B1">Aiuchi et al., 2022</xref>; <xref ref-type="bibr" rid="B2">Allegra et al., 2018</xref>; <xref ref-type="bibr" rid="B4">Bartelink et al., 2013</xref>; <xref ref-type="bibr" rid="B5">Benedict et al., 2023</xref>; <xref ref-type="bibr" rid="B6">Blanco-Dorado et al., 2019</xref>; <xref ref-type="bibr" rid="B8">Boast et al., 2016</xref>; <xref ref-type="bibr" rid="B11">Cabral-Galeano et al., 2015</xref>; <xref ref-type="bibr" rid="B14">Chaudhri et al., 2020</xref>; <xref ref-type="bibr" rid="B15">Chen C. Y. et al., 2022</xref>; <xref ref-type="bibr" rid="B16">Chen J. et al., 2022</xref>; <xref ref-type="bibr" rid="B18">Chen T. T. et al., 2022</xref>; <xref ref-type="bibr" rid="B20">Chen X. et al., 2022</xref>; <xref ref-type="bibr" rid="B22">Cheng et al., 2020</xref>; <xref ref-type="bibr" rid="B23">Choi et al., 2013</xref>; <xref ref-type="bibr" rid="B24">Chuwongwattana et al., 2016</xref>; <xref ref-type="bibr" rid="B25">Cojutti et al., 2016</xref>; <xref ref-type="bibr" rid="B29">Dolton et al., 2012</xref>; <xref ref-type="bibr" rid="B30">Dorado et al., 2020</xref>; <xref ref-type="bibr" rid="B31">Dote et al., 2016</xref>; <xref ref-type="bibr" rid="B32">Duehlmeyer et al., 2021</xref>; <xref ref-type="bibr" rid="B33">Ebrahimpour et al., 2017</xref>; <xref ref-type="bibr" rid="B35">Fan et al., 2022</xref>; <xref ref-type="bibr" rid="B39">Hashemizadeh et al., 2017</xref>; <xref ref-type="bibr" rid="B40">Hoenigl et al., 2013</xref>; <xref ref-type="bibr" rid="B42">Hu et al., 2018</xref>; <xref ref-type="bibr" rid="B44">Hu et al., 2023</xref>; <xref ref-type="bibr" rid="B45">Huang et al., 2023</xref>; <xref ref-type="bibr" rid="B46">Huang et al., 2020</xref>; <xref ref-type="bibr" rid="B48">Jia et al., 2021</xref>; <xref ref-type="bibr" rid="B50">Kang et al., 2015</xref>; <xref ref-type="bibr" rid="B52">Kim et al., 2014</xref>; <xref ref-type="bibr" rid="B57">Lempers et al., 2019</xref>; <xref ref-type="bibr" rid="B59">Li et al., 2020</xref>; <xref ref-type="bibr" rid="B62">Li et al., 2023</xref>; <xref ref-type="bibr" rid="B65">Liu et al., 2017</xref>; <xref ref-type="bibr" rid="B68">Mafuru et al., 2021</xref>; <xref ref-type="bibr" rid="B69">Miao et al., 2019</xref>; <xref ref-type="bibr" rid="B73">Myrianthefs et al., 2010</xref>; <xref ref-type="bibr" rid="B77">Pieper et al., 2012</xref>; <xref ref-type="bibr" rid="B81">Ronda et al., 2023</xref>; <xref ref-type="bibr" rid="B82">Ruiz et al., 2019</xref>; <xref ref-type="bibr" rid="B84">Saini et al., 2014</xref>; <xref ref-type="bibr" rid="B85">Shao et al., 2017</xref>; <xref ref-type="bibr" rid="B86">Shen et al., 2022</xref>; <xref ref-type="bibr" rid="B89">Soler-Palacin et al., 2012</xref>; <xref ref-type="bibr" rid="B93">Takahashi et al., 2020</xref>; <xref ref-type="bibr" rid="B95">Tian et al., 2021</xref>; <xref ref-type="bibr" rid="B97">Troke et al., 2011</xref>; <xref ref-type="bibr" rid="B98">Valle-T-Figueras et al., 2021</xref>; <xref ref-type="bibr" rid="B102">Wei et al., 2019</xref>; <xref ref-type="bibr" rid="B103">Yan et al., 2018</xref>; <xref ref-type="bibr" rid="B104">Yang et al., 2023</xref>; <xref ref-type="bibr" rid="B105">Ye et al., 2022</xref>; <xref ref-type="bibr" rid="B106">Yi et al., 2017</xref>; <xref ref-type="bibr" rid="B107">Zeng et al., 2020</xref>; <xref ref-type="bibr" rid="B108">Zhang et al., 2023</xref>; <xref ref-type="bibr" rid="B109">Zhao et al., 2021a</xref>; <xref ref-type="bibr" rid="B110">Zhao et al., 2021b</xref>; <xref ref-type="bibr" rid="B111">Zhao Y. C. et al., 2021</xref>; <xref ref-type="bibr" rid="B112">Zhou et al., 2020</xref>). Of the 60 articles, 58 studies were included in the quantitative synthesis. <xref ref-type="fig" rid="F1">Figure 1</xref> shows the specific screening process of the literature.</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>PRISMA flow diagram.</p>
</caption>
<graphic xlink:href="fphar-15-1368274-g001.tif"/>
</fig>
</sec>
<sec id="s3-2">
<title>3.2 Study characteristics</title>
<p>All included studies were cross-sectional studies. The characteristics of the included studies are detailed in <xref ref-type="table" rid="T1">Table 1</xref>. Of these, 20 studies performed multiple linear regression and reported coefficients (<xref ref-type="bibr" rid="B2">Allegra et al., 2018</xref>; <xref ref-type="bibr" rid="B18">Chen T. T. et al., 2022</xref>; <xref ref-type="bibr" rid="B19">Chen W. Q. et al., 2022</xref>; <xref ref-type="bibr" rid="B25">Cojutti et al., 2016</xref>; <xref ref-type="bibr" rid="B29">Dolton et al., 2012</xref>; <xref ref-type="bibr" rid="B30">Dorado et al., 2020</xref>; <xref ref-type="bibr" rid="B31">Dote et al., 2016</xref>; <xref ref-type="bibr" rid="B35">Fan et al., 2022</xref>; <xref ref-type="bibr" rid="B39">Hashemizadeh et al., 2017</xref>; <xref ref-type="bibr" rid="B42">Hu et al., 2018</xref>; <xref ref-type="bibr" rid="B44">Hu et al., 2023</xref>; <xref ref-type="bibr" rid="B68">Mafuru et al., 2021</xref>; <xref ref-type="bibr" rid="B81">Ronda et al., 2023</xref>; <xref ref-type="bibr" rid="B93">Takahashi et al., 2020</xref>; <xref ref-type="bibr" rid="B95">Tian et al., 2021</xref>; <xref ref-type="bibr" rid="B105">Ye et al., 2022</xref>; <xref ref-type="bibr" rid="B107">Zeng et al., 2020</xref>; <xref ref-type="bibr" rid="B109">Zhao et al., 2021a</xref>; <xref ref-type="bibr" rid="B110">Zhao et al., 2021b</xref>; <xref ref-type="bibr" rid="B111">Zhao Y. C. et al., 2021</xref>). In contrast, 53 studies provided data on the number of patients achieving the therapeutic range of plasma voriconazole concentration (<xref ref-type="bibr" rid="B1">Aiuchi et al., 2022</xref>; <xref ref-type="bibr" rid="B4">Bartelink et al., 2013</xref>; <xref ref-type="bibr" rid="B5">Benedict et al., 2023</xref>; <xref ref-type="bibr" rid="B8">Boast et al., 2016</xref>; <xref ref-type="bibr" rid="B11">Cabral-Galeano et al., 2015</xref>; <xref ref-type="bibr" rid="B14">Chaudhri et al., 2020</xref>; <xref ref-type="bibr" rid="B15">Chen C. Y. et al., 2022</xref>; <xref ref-type="bibr" rid="B16">Chen J. et al., 2022</xref>; <xref ref-type="bibr" rid="B18">Chen T. T. et al., 2022</xref>; <xref ref-type="bibr" rid="B20">Chen X. et al., 2022</xref>; <xref ref-type="bibr" rid="B22">Cheng et al., 2020</xref>; <xref ref-type="bibr" rid="B23">Choi et al., 2013</xref>; <xref ref-type="bibr" rid="B24">Chuwongwattana et al., 2016</xref>; <xref ref-type="bibr" rid="B30">Dorado et al., 2020</xref>; <xref ref-type="bibr" rid="B32">Duehlmeyer et al., 2021</xref>; <xref ref-type="bibr" rid="B33">Ebrahimpour et al., 2017</xref>; <xref ref-type="bibr" rid="B40">Hoenigl et al., 2013</xref>; <xref ref-type="bibr" rid="B42">Hu et al., 2018</xref>; <xref ref-type="bibr" rid="B44">Hu et al., 2023</xref>; <xref ref-type="bibr" rid="B45">Huang et al., 2023</xref>; <xref ref-type="bibr" rid="B46">Huang et al., 2020</xref>; <xref ref-type="bibr" rid="B48">Jia et al., 2021</xref>; <xref ref-type="bibr" rid="B50">Kang et al., 2015</xref>; <xref ref-type="bibr" rid="B52">Kim et al., 2014</xref>; <xref ref-type="bibr" rid="B57">Lempers et al., 2019</xref>; <xref ref-type="bibr" rid="B59">Li et al., 2020</xref>; <xref ref-type="bibr" rid="B62">Li et al., 2023</xref>; <xref ref-type="bibr" rid="B69">Miao et al., 2019</xref>; <xref ref-type="bibr" rid="B73">Myrianthefs et al., 2010</xref>; <xref ref-type="bibr" rid="B77">Pieper et al., 2012</xref>; <xref ref-type="bibr" rid="B81">Ronda et al., 2023</xref>; <xref ref-type="bibr" rid="B82">Ruiz et al., 2019</xref>; <xref ref-type="bibr" rid="B84">Saini et al., 2014</xref>; <xref ref-type="bibr" rid="B85">Shao et al., 2017</xref>; <xref ref-type="bibr" rid="B86">Shen et al., 2022</xref>; <xref ref-type="bibr" rid="B89">Soler-Palacin et al., 2012</xref>; <xref ref-type="bibr" rid="B93">Takahashi et al., 2020</xref>; <xref ref-type="bibr" rid="B95">Tian et al., 2021</xref>; <xref ref-type="bibr" rid="B97">Troke et al., 2011</xref>; <xref ref-type="bibr" rid="B98">Valle-T-Figueras et al., 2021</xref>; <xref ref-type="bibr" rid="B102">Wei et al., 2019</xref>; <xref ref-type="bibr" rid="B103">Yan et al., 2018</xref>; <xref ref-type="bibr" rid="B104">Yang et al., 2023</xref>; <xref ref-type="bibr" rid="B105">Ye et al., 2022</xref>; <xref ref-type="bibr" rid="B106">Yi et al., 2017</xref>; <xref ref-type="bibr" rid="B107">Zeng et al., 2020</xref>; <xref ref-type="bibr" rid="B108">Zhang et al., 2023</xref>; <xref ref-type="bibr" rid="B110">Zhao et al., 2021b</xref>; <xref ref-type="bibr" rid="B111">Zhao Y. C. et al., 2021</xref>; <xref ref-type="bibr" rid="B112">Zhou et al., 2020</xref>; <xref ref-type="bibr" rid="B7">Blanco-Dorado et al., 2020</xref>).</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Characteristics of included studies.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">Study</th>
<th align="center">Country</th>
<th align="center">Type</th>
<th align="center">Age (mean or median)</th>
<th align="center">Male (%)</th>
<th align="center">Type of treatment setting</th>
<th align="center">Method</th>
<th align="center">Indications</th>
<th align="center">Duration (days) (mean or median)</th>
<th align="center">No. of patients (samples)</th>
<th align="center">Dose adjustments</th>
<th align="center">No. of samples within therapeutic range (%)</th>
<th align="center">Range (mg/L)</th>
<th align="center">Multiple linear regression</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">
<xref ref-type="bibr" rid="B1">Aiuchi et al. (2022)</xref>
</td>
<td align="center">Japan</td>
<td align="center">Cross-sectional</td>
<td align="center">67.2 &#xb1; 14.1</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">UPLC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">36 (56)</td>
<td align="center">No</td>
<td align="center">35 (62.5)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B2">Allergra et al. (2018)</xref>
</td>
<td align="center">Italy</td>
<td align="center">Cross-sectional</td>
<td align="center">10 (7&#x2013;14)</td>
<td align="center">62.9</td>
<td align="center">&#x2014;</td>
<td align="center">HLPC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">233 (233)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B4">Bartelink et al. (2013)</xref>
</td>
<td align="center">Nether lands</td>
<td align="center">Cross-sectional</td>
<td align="center">7.3 (0.3&#x2013;20)</td>
<td align="center">59</td>
<td align="center">Pediatric HSCT</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">39 (6&#x2013;415)</td>
<td align="center">61 (61)</td>
<td align="center">Yes</td>
<td align="center">49 (80.4)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B5">Benedict et al. (2023)</xref>
</td>
<td align="center">America</td>
<td align="center">Cross-sectional</td>
<td align="center">58.0 (42&#x2013;68)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">296 (296)</td>
<td align="center">Yes</td>
<td align="center">186 (62.9)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B6">Blanco-Dorado et al. (2019)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">68 (19&#x2013;93)</td>
<td align="center">55.1</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">26 (4&#x2013;185)</td>
<td align="center">78 (78)</td>
<td align="center">No</td>
<td align="center">34 (44.8)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B8">Boast et al. (2016)</xref>
</td>
<td align="center">Austria</td>
<td align="center">Cross-sectional</td>
<td align="center">10.5</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">72.5 (4&#x2013;567)</td>
<td align="center">55 (120)</td>
<td align="center">Yes</td>
<td align="center">53 (44.2)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B11">Cabral-Galeano et al. (2015)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">55 (35.7&#x2013;60.7)</td>
<td align="center">59.6</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">56 (21&#x2013;98)</td>
<td align="center">52 (52)</td>
<td align="center">Yes</td>
<td align="center">36 (69.2)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B14">Chaudhri et al. (2020)</xref>
</td>
<td align="center">Australia</td>
<td align="center">Cross-sectional</td>
<td align="center">57 (21&#x2013;89)</td>
<td align="center">55.6</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">9 (1&#x2013;64)</td>
<td align="center">90 (101)</td>
<td align="center">Yes</td>
<td align="center">58 (57)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B15">Chen C. Y. et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">59 (47&#x2013;68)</td>
<td align="center">65.5</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">15 (8&#x2013;16.5)</td>
<td align="center">325 (325)</td>
<td align="center">No</td>
<td align="center">217 (66.8)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B16">Chen J. et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">6.0 (3.0&#x2013;9.0)</td>
<td align="center">59.3</td>
<td align="center">Pediatric HSCT</td>
<td align="center">HLPC-MS/MS</td>
<td align="center">NA</td>
<td align="center">59 (23&#x2013;149)</td>
<td align="center">91 (682)</td>
<td align="center">Yes</td>
<td align="center">422 (61.9)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B18">Chen T. T. et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">39.71 &#xb1; 14.14</td>
<td align="center">85.7</td>
<td align="center">AIDS</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">28 (46)</td>
<td align="center">Yes</td>
<td align="center">16 (57.1)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B20">Chen X. et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">6 (1&#x2013;15)</td>
<td align="center">60.6</td>
<td align="center">Pediatrics</td>
<td align="center">2D-HPLC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">94 (253)</td>
<td align="center">No</td>
<td align="center">40 (42.6)</td>
<td align="center">2.0&#x2013;5.0</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B22">Cheng et al. (2020)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">55.4</td>
<td align="center">64.5</td>
<td align="center">&#x2014;</td>
<td align="center">LC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">166 (317)</td>
<td align="center">Yes</td>
<td align="center">213 (67.2)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B23">Choi et al. (2013)</xref>
</td>
<td align="center">Korea</td>
<td align="center">Cross-sectional</td>
<td align="center">12.2 (1.2&#x2013;18.9)</td>
<td align="center">66.7</td>
<td align="center">Oncology</td>
<td align="center">HLPC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">60 (10&#x2013;305)</td>
<td align="center">27 (193)</td>
<td align="center">Yes</td>
<td align="center">123 (63.7)</td>
<td align="center">1.0&#x2013;6.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B24">Chuwongwattana et al. (2016)</xref>
</td>
<td align="center">Thailand</td>
<td align="center">Cross-sectional</td>
<td align="center">57 (18&#x2013;88)</td>
<td align="center">53</td>
<td align="center">&#x2014;</td>
<td align="center">LC-MS/MS</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">115 (285)</td>
<td align="center">NA</td>
<td align="center">151 (52.98)</td>
<td align="center">1.0&#x2013;4.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B25">Cojutti et al. (2016)</xref>
</td>
<td align="center">Italy</td>
<td align="center">Cross-sectional</td>
<td align="center">54 (41&#x2013;62)</td>
<td align="center">61.4</td>
<td align="center">Hematology</td>
<td align="center">HLPC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">36 (18&#x2013;81)</td>
<td align="center">83 (199)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B29">Dolton et al. (2012)</xref>
</td>
<td align="center">Australia</td>
<td align="center">Cross-sectional</td>
<td align="center">54 (18&#x2013;88)</td>
<td align="center">57.7</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">201 (783)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B30">Dorado et al. (2020)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">68 (19&#x2013;93)</td>
<td align="center">55.1</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">78 (78)</td>
<td align="center">No</td>
<td align="center">34 (44.8)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B31">Dote et al. (2016)</xref>
</td>
<td align="center">Japan</td>
<td align="center">Cross-sectional</td>
<td align="center">70.8 &#xb1; 11.0</td>
<td align="center">79.4</td>
<td align="center">Hematology<break/>Pulmonology<break/>Rheumatology<break/>Other</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">63 (77)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B32">Duehlmeyer et al. (2021)</xref>
</td>
<td align="center">America</td>
<td align="center">Cross-sectional</td>
<td align="center">&#x3c;20</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">39 (77)</td>
<td align="center">Yes</td>
<td align="center">39 (50.7)</td>
<td align="center">2&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B33">Ebrahimpour et al. (2017)</xref>
</td>
<td align="center">Iran</td>
<td align="center">Cross-sectional</td>
<td align="center">34.6 &#xb1; 11.2</td>
<td align="center">51.4</td>
<td align="center">Hematology-oncology and stem cell research center</td>
<td align="center">HPLC</td>
<td align="center">NA</td>
<td align="center">&#x2014;</td>
<td align="center">37 (37)</td>
<td align="center">No</td>
<td align="center">27 (73.0)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B35">Fan et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">6.5 &#xb1; 3.7</td>
<td align="center">55.9</td>
<td align="center">Hematology</td>
<td align="center">UPLC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">68 (68)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B39">Hashemizadeh et al. (2017)</xref>
</td>
<td align="center">Iran</td>
<td align="center">Cross-sectional</td>
<td align="center">36 &#xb1; 13.71</td>
<td align="center">42.3</td>
<td align="center">Liver transplant center</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">39 (21&#x2013;50)</td>
<td align="center">104 (832)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B40">Hoenigl et al. (2013)</xref>
</td>
<td align="center">Austria</td>
<td align="center">Cross-sectional</td>
<td align="center">55.94</td>
<td align="center">59</td>
<td align="center">ICU<break/>Hematological malignancy</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">61 (221)</td>
<td align="center">Yes</td>
<td align="center">79 (36)</td>
<td align="center">1.5&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B42">Hu et al. (2018)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">9 (3&#x2013;14)</td>
<td align="center">51.7</td>
<td align="center">Hematology</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">23.5 (4&#x2013;159)</td>
<td align="center">42 (138)</td>
<td align="center">Yes</td>
<td align="center">28 (66.7)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B44">Hu et al. (2023)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">13 (2&#x2013;14)</td>
<td align="center">61.1</td>
<td align="center">Pediatric hematology</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">15 (3&#x2013;148)</td>
<td align="center">131 (250)</td>
<td align="center">Yes</td>
<td align="center">129 (51.6)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B45">Huang et al. (2023)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">56 &#xb1; 14.91</td>
<td align="center">56.6</td>
<td align="center">Hematology</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">136 (136)</td>
<td align="center">Yes</td>
<td align="center">90 (66.2)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B46">Huang et al. (2020)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">Control 39.0 (4&#x2013;68)<break/>LAN<break/>39.0 (4&#x2013;68)<break/>OME<break/>44.0 (9&#x2013;78)<break/>PAN<break/>39.5 (3&#x2013;84)</td>
<td align="center">57.7</td>
<td align="center">Hematology</td>
<td align="center">2D-HPLC</td>
<td align="center">NA</td>
<td align="center">&#x2014;</td>
<td align="center">194 (194)</td>
<td align="center">Yes</td>
<td align="center">152 (78.4)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B48">Jia et al. (2021)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">51.47 &#xb1; 17.55</td>
<td align="center">58</td>
<td align="center">&#x2014;</td>
<td align="center">2D-HPLC</td>
<td align="center">NA</td>
<td align="center">&#x2014;</td>
<td align="center">231 (918)</td>
<td align="center">Yes</td>
<td align="center">714 (77.8)</td>
<td align="center">0.5&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B50">Kang et al. (2015)</xref>
</td>
<td align="center">Korea</td>
<td align="center">Cross-sectional</td>
<td align="center">8.7 &#xb1; 6.3</td>
<td align="center">58.1</td>
<td align="center">&#x2014;</td>
<td align="center">HLPC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">31 (271)</td>
<td align="center">Yes</td>
<td align="center">180 (66.7)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B52">Kim et al. (2014)</xref>
</td>
<td align="center">Korea</td>
<td align="center">Cross-sectional</td>
<td align="center">54 (23&#x2013;81)</td>
<td align="center">67.2</td>
<td align="center">Oncology</td>
<td align="center">&#x2014;</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">64 (354)</td>
<td align="center">Yes</td>
<td align="center">48 (75)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B57">Lempers et al. (2019)</xref>
</td>
<td align="center">Nether lands</td>
<td align="center">Cross-sectional</td>
<td align="center">7.0 (1.2&#x2013;18.5)</td>
<td align="center">38.1</td>
<td align="center">Pediatric hematology-oncology</td>
<td align="center">HPLC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">118 (17&#x2013;866)</td>
<td align="center">21 (485)</td>
<td align="center">Yes</td>
<td align="center">282 (58.1)</td>
<td align="center">1.0&#x2013;6.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B59">Li et al. (2020)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">62 (47.5&#x2013;76.5)</td>
<td align="center">74.4</td>
<td align="center">ICU</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis (19.2) treatment (80.8)</td>
<td align="center">14</td>
<td align="center">125 (125)</td>
<td align="center">No</td>
<td align="center">67 (53.6)</td>
<td align="center">1.5&#x2013;4.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B62">Li et al. (2023)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">alb &#x3c; 35&#xa0;g/L:61 alb &#x2265; 35&#xa0;g/L:50</td>
<td align="center">59.2</td>
<td align="center">&#x2014;</td>
<td align="center">LC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">120 (275)</td>
<td align="center">Yes</td>
<td align="center">174 (71.9)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B65">Liu et al. (2017)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">2.1 (0.1&#x2013;11.1)</td>
<td align="center">75.2</td>
<td align="center">Pediatrics</td>
<td align="center">LC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">107 (126)</td>
<td align="center">No</td>
<td align="center">51 (47.7)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B68">Mafuru et al. (2021)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">36 (25&#x2013;51)</td>
<td align="center">72.8</td>
<td align="center">Hematology</td>
<td align="center">LC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">114 (250)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B69">Miao et al. (2019)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">49.5 (39.5&#x2013;62.3)</td>
<td align="center">64.2</td>
<td align="center">&#x2014;</td>
<td align="center">UPLC-MS/MS</td>
<td align="center">NA</td>
<td align="center">&#x2014;</td>
<td align="center">106 (152)</td>
<td align="center">Yes</td>
<td align="center">107 (71.7)</td>
<td align="center">1.5&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B73">Myrianthefs et al. (2010)</xref>
</td>
<td align="center">Greece</td>
<td align="center">Cross-sectional</td>
<td align="center">62.3 &#xb1; 22</td>
<td align="center">80.0</td>
<td align="center">ICU</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">18 (18)</td>
<td align="center">No</td>
<td align="center">6 (33.3)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B77">Pieper et al. (2012)</xref>
</td>
<td align="center">Germany</td>
<td align="center">Cross-sectional</td>
<td align="center">10.2</td>
<td align="center">56.8</td>
<td align="center">Pediatrics</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">40 (6&#x2013;1,002)</td>
<td align="center">74 (251)</td>
<td align="center">NA</td>
<td align="center">86 (34.6)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B81">Ronda et al. (2023)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">58 &#xb1; 10</td>
<td align="center">62.5</td>
<td align="center">ICU</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">16.5</td>
<td align="center">24 (53)</td>
<td align="center">Yes</td>
<td align="center">26 (49.1)</td>
<td align="center">1.0&#x2013;5.0</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B82">Ruiz et al. (2019)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">55.3 (12.6)</td>
<td align="center">54.5</td>
<td align="center">ICU</td>
<td align="center">EIA</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">33 (33)</td>
<td align="center">No</td>
<td align="center">15 (45.5)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B84">Saini et al. (2014)</xref>
</td>
<td align="center">Canada</td>
<td align="center">Cross-sectional</td>
<td align="center">58 (19&#x2013;80)</td>
<td align="center">55.1</td>
<td align="center">Hematology</td>
<td align="center">LC-MS/MS</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">69 (69)</td>
<td align="center">No</td>
<td align="center">40 (58.0)</td>
<td align="center">0.5&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B85">Shao et al. (2017)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">49.6 &#xb1; 18.2</td>
<td align="center">59.3</td>
<td align="center">Hematology</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">86 (106)</td>
<td align="center">Yes</td>
<td align="center">67 (63.2)</td>
<td align="center">1.0&#x2013;4.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B86">Shen et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">63 (52&#x2013;72)</td>
<td align="center">72.9</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">140 (140)</td>
<td align="center">Yes</td>
<td align="center">117 (84.1)</td>
<td align="center">1.5&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B89">Soler-Palacin et al. (2012)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">10 (1&#x2013;17)</td>
<td align="center">53.3</td>
<td align="center">Pediatrics</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">42 (7&#x2013;588)</td>
<td align="center">30 (196)</td>
<td align="center">Yes</td>
<td align="center">84 (42.9)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B93">Takahashi et al. (2020)</xref>
</td>
<td align="center">America</td>
<td align="center">Cross-sectional</td>
<td align="center">11.7 &#xb1; 5.3</td>
<td align="center">65.9</td>
<td align="center">HSCT</td>
<td align="center">LC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">44 (44)</td>
<td align="center">No</td>
<td align="center">16 (36)</td>
<td align="center">1.5&#x2013;5.0</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B95">Tian et al. (2021)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">10.5 (0.67&#x2013;18.0)</td>
<td align="center">63.9</td>
<td align="center">Pediatrics</td>
<td align="center">UPLC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">108 (348)</td>
<td align="center">Yes</td>
<td align="center">221 (63.8)</td>
<td align="center">0.5&#x2013;5.0</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B97">Troke et al. (2011)</xref>
</td>
<td align="center">New Zealand</td>
<td align="center">Cross-sectional</td>
<td align="center">44 (12&#x2013;90)</td>
<td align="center">66.2</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">825 (825)</td>
<td align="center">Yes</td>
<td align="center">591 (71.6)</td>
<td align="center">0.5&#x2013;5.0</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B98">Valle-T-Figueras et al. (2021)</xref>
</td>
<td align="center">Spain</td>
<td align="center">Cross-sectional</td>
<td align="center">9 (6&#x2013;10)</td>
<td align="center">55.6</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">80.5 (15&#x2013;117)</td>
<td align="center">27 (229)</td>
<td align="center">Yes</td>
<td align="center">147 (64.2)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B102">Wei et al. (2019)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">57 (31&#x2013;67)</td>
<td align="center">59.7</td>
<td align="center">Hematology<break/>ICU</td>
<td align="center">HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">67 (119)</td>
<td align="center">NA</td>
<td align="center">70 (59)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B103">Yan et al. (2018)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">41.7</td>
<td align="center">75.6</td>
<td align="center">&#x2014;</td>
<td align="center" style="color:#1F1F1F">2D-HPLC</td>
<td align="center">NA</td>
<td align="center">&#x2014;</td>
<td align="center">349 (349)</td>
<td align="center">No</td>
<td align="center">258 (74.0)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B104">Yang et al. (2023)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">66 (57&#x2013;71)</td>
<td align="center">72.3</td>
<td align="center">Hematology<break/>Respiratory medicine<break/>Emergency/intensive care medicine<break/>Oncology<break/>Others</td>
<td align="center">2D-HPLC</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">83 (83)</td>
<td align="center">No</td>
<td align="center">66 (79.5)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B105">Ye et al. (2022)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">58.1 &#xb1; 17.0</td>
<td align="center">74.5</td>
<td align="center">ICU</td>
<td align="center">UPLC-MS/MS</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">132 (132)</td>
<td align="center">Yes</td>
<td align="center">63 (47.7)</td>
<td align="center">2.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B106">Yi et al. (2017)</xref>
</td>
<td align="center">America</td>
<td align="center">Cross-sectional</td>
<td align="center">50 (33&#x2013;60)</td>
<td align="center">49.2</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">122 (250)</td>
<td align="center">Yes</td>
<td align="center">134 (54)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B107">Zeng et al. (2020)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">40 &#xb1; 18</td>
<td align="center">60.5</td>
<td align="center">&#x2014;</td>
<td align="center">HLPC-MS/MS</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">170 (510)</td>
<td align="center">Yes</td>
<td align="center">342 (67.1)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B108">Zhang et al. (2023)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">53.2 &#xb1; 13.4</td>
<td align="center">78.8</td>
<td align="center">&#x2014;</td>
<td align="center">HPLC</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">66 (66)</td>
<td align="center">No</td>
<td align="center">48 (72.7)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B109">Zhao et al. (2021a)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">49.4 &#xb1; 11.7</td>
<td align="center">90.7</td>
<td align="center">&#x2014;</td>
<td align="center">2D-HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">12 (5&#x2013;45)</td>
<td align="center">43 (144)</td>
<td align="center">&#x2014;</td>
<td align="center">&#x2014;</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B110">Zhao et al. (2021b)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">52.0 (40.0&#x2013;64.0)</td>
<td align="center">70.7</td>
<td align="center">&#x2014;</td>
<td align="center">2D-HPLC</td>
<td align="center">Treatment</td>
<td align="center">&#x2014;</td>
<td align="center">676 (1,212)</td>
<td align="center">Yes</td>
<td align="center">741 (61.1)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B111">Zhao Y. C. et al. (2021)</xref>
</td>
<td align="center">China</td>
<td align="center">Cross-sectional</td>
<td align="center">&#x2014;</td>
<td align="center">52.1</td>
<td align="center">Pediatric</td>
<td align="center">2D-HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">94 (145)</td>
<td align="center">Yes</td>
<td align="center">78 (53.8)</td>
<td align="center">1.0&#x2013;5.5</td>
<td align="center">Yes</td>
</tr>
<tr>
<td align="center">
<xref ref-type="bibr" rid="B112">Zhou et al. (2020)</xref>
</td>
<td align="center">Singapore</td>
<td align="center">Cross-sectional</td>
<td align="center">56 &#xb1; 14</td>
<td align="center">67.1</td>
<td align="center">&#x2014;</td>
<td align="center">2D-HPLC</td>
<td align="center">Prophylaxis treatment</td>
<td align="center">&#x2014;</td>
<td align="center">70 (70)</td>
<td align="center">No</td>
<td align="center">32 (45.7)</td>
<td align="center">2.0&#x2013;5.5</td>
<td align="center">No</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Abbreviations: UPLC, ultraperformance liquid chromatography; HPLC, high-performance liquid chromatography system; HPLC-MS, high performance liquid chromatography-mass spectrometry; HPLC-MS/MS, high-performance liquid chromatography-tandem mass spectrometry; LC-MS/MS, liquid chromatography tandem-mass spectrometry; UPLC&#x2013;QTOF/MS, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry; 2D-HPLC, automatic two-dimensional liquid chromatography; EIA, enzyme immunoassay technique; HSCT, hematopoietic stem cell transplantation; ICU, intensive care unit; PAD, photodiode array detection; LAN, lansoprazole; OME, omeprazole; PAN, pantoprazole; Alb, albumin.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>The total count of patients and blood samples in these studies was 7,319 and 14,646, respectively. The recommended concentration ranges for voriconazole varied between studies and included 1.0&#x2013;5.5&#xa0;mg/L (n &#x3d; 24), 1.0&#x2013;5.0&#xa0;mg/L (n &#x3d; 10), 0.5&#x2013;5.0&#xa0;mg/L (n &#x3d; 3), 1.5&#x2013;5.5&#xa0;mg/L (n &#x3d; 3), 2.0&#x2013;5.5&#xa0;mg/L (n &#x3d; 3), 1.0&#x2013;4.0&#xa0;mg/L (n &#x3d; 2), and 1.0&#x2013;6.0&#xa0;mg/L (n &#x3d; 2). Additionally, there was one study each for the ranges 1.5&#x2013;4.0&#xa0;mg/L, 0.5&#x2013;5.5&#xa0;mg/L, and 1.5&#x2013;5.0&#xa0;mg/L. Regarding dose adjustments, 33 studies implemented them, 16 did not, and 3 did not specify. Among the 33 studies that adjusted doses, one followed Australian guideline, three adhered to Chinese guidelines, 16 based adjustments on TDM, clinical efficacy, adverse events, and clinician experience, 13 did not specify the adjustment methodology, and only five studies explicitly recorded their dose adjustment plan. Details of dose adjustments are shown in <xref ref-type="sec" rid="s11">Supplementary Table S2</xref>.</p>
</sec>
<sec id="s3-3">
<title>3.3 Study quality assessment</title>
<p>The 60 studies included in this analysis were all cross-sectional studies. Regarding the quality assessment based on the AHRQ scoring system, each study scored 5 or higher. Specifically, 4 studies were categorized as high quality, while the remaining 56 were considered moderate quality. Of these, 4 studies scored 8, 30 scored 7, 24 scored 6, and only 2 scored 5. Detailed results of the quality assessment for each study are shown in <xref ref-type="sec" rid="s11">Supplementary Table S3</xref>.</p>
</sec>
<sec id="s3-4">
<title>3.4 Prevalence of patients reaching the therapeutic range of plasma concentration</title>
<p>Among the 60 included studies, 52 reported the prevalence of patients who achieved the plasma voriconazole concentration therapeutic range. The highest and lowest recorded prevalences were 0.84 and 0.33, respectively. A sensitivity analysis led to the exclusion of one study that significantly skewed the results, as shown in <xref ref-type="fig" rid="F2">Figure 2</xref>. After removing this outlier, the pooled prevalence of patients reaching therapeutic voriconazole concentration was 59% (95% CI: 56%&#x2013;62%). In the subgroup analysis according to the method of dose adjustment, the pooled prevalence was 56% (95% CI: 50%&#x2013;63%) in studies without dose adjustment and 61% (95% CI: 56%&#x2013;66%) in studies with dose adjustment according to TDM, and the pooled prevalence of guideline-adjusted dose studies was 62% (95% CI: 58%&#x2013;66%), as shown in <xref ref-type="fig" rid="F3">Figure 3</xref>. In the subgroup analysis according to study cohort, the pooled prevalence of adult patients was 61% (95% CI: 56%&#x2013;65%), and the pooled prevalence of children patients was 55% (95% CI: 50%&#x2013;60%), as shown in <xref ref-type="fig" rid="F4">Figure 4</xref>.</p>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Sensitivity analysis.</p>
</caption>
<graphic xlink:href="fphar-15-1368274-g002.tif"/>
</fig>
<fig id="F3" position="float">
<label>FIGURE 3</label>
<caption>
<p>Prevalence of patients reaching the therapeutic range of voriconazole plasma concentration across the method of dose adjustment.</p>
</caption>
<graphic xlink:href="fphar-15-1368274-g003.tif"/>
</fig>
<fig id="F4" position="float">
<label>FIGURE 4</label>
<caption>
<p>Prevalence of patients reaching the therapeutic range of voriconazole plasma concentration across study cohort.</p>
</caption>
<graphic xlink:href="fphar-15-1368274-g004.tif"/>
</fig>
<p>The meta-analysis revealed high heterogeneity in all included studies. To investigate the sources of this heterogeneity, a meta-regression was performed, considering factors such as sex, country, dose adjustments, therapeutic range, type of treatment settings, and the analytical method used for measuring voriconazole. The results identified the therapeutic range, sex, and analytical method as significant contributors to the heterogeneity. Detailed findings from the meta-regression are presented in <xref ref-type="sec" rid="s11">Supplementary Figure S1</xref>.</p>
</sec>
<sec id="s3-5">
<title>3.5 Associated factors with voriconazole concentration</title>
<p>Of the 60 studies, 20 conducted multiple linear regression and reported coefficients. However, only 17 studies provided coefficients and standard errors derived from regression analyses. <xref ref-type="table" rid="T2">Table 2</xref> details the specific factors reported in each study. Due to consistency in units and references between studies, we pooled and analysed respectively the coefficients and standard errors of associated factors about plasma voriconazole concentration in children and adult cohorts. These factors included age, sex, dosage, administration modes (oral and intravenous), albumin (ALB), blood urea nitrogen (BUN), total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), use of proton pump inhibitors (PPIs), omeprazole, pantoprazole, glucocorticoids, methylprednisolone, and dexamethasone. <xref ref-type="fig" rid="F5">Figure 5</xref> presents details of all the potential confounders identified in these studies.</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Factor associated with voriconazole plasma concentration reported by each study.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Variable in multiple linear regression</th>
<th align="left">Risk factors</th>
<th align="left">Studies</th>
<th align="left">No. of patients (concentrations)</th>
<th align="left">Study cohort</th>
<th align="left">R<sup>2</sup>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Sex, ethnicity, voriconazole dose (mg/kg), genetic factors (SLCO1B3, ABCG2, ABCC2 and ABCB1 gene polymorphisms)</td>
<td align="left">Ethnicity, sex, genetic factors (SLCO1B3, ABCG2, ABCC2 and ABCB1 gene polymorphisms)</td>
<td align="left">
<xref ref-type="bibr" rid="B2">Allergra et al. (2018)</xref>
</td>
<td align="left">233</td>
<td align="left">Pediatric patients</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">Drug interaction, ALB (g/L), sex, weight (kg), child-pugh classification</td>
<td align="left">Drug interaction, ALB (g/L), sex, weight (kg), child-pugh classification</td>
<td align="left">
<xref ref-type="bibr" rid="B18">Chen T. T. et al. (2022)</xref>
</td>
<td align="left">28 (46)</td>
<td align="left">AIDS patients</td>
<td align="left">0.406</td>
</tr>
<tr>
<td align="left">Age, sex, weight (kg), ALT (U/L) CYP2C19 gene polymorphism, drug administration</td>
<td align="left">Age, CYP2C19 gene polymorphism</td>
<td align="left">
<xref ref-type="bibr" rid="B19">Chen W. Q. et al. (2022)</xref>
</td>
<td align="left">94 (253)</td>
<td align="left">Pediatric patients</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">Omeprazole, pantoprazole, methylprednisolone, dexamethasone, phenobarbital, rifampin, carbamazepine</td>
<td align="left">Omeprazole, pantoprazole, dexamethasone, rifampin, methylprednisolone, carbamazepine phenobarbital</td>
<td align="left">
<xref ref-type="bibr" rid="B25">Cojutti et al. (2016)</xref>
</td>
<td align="left">83 (199)</td>
<td align="left">Adults</td>
<td align="left"/>
</tr>
<tr>
<td align="left">PO, age, weight (kg), daily dose (mg), CYP2C19inducer (phenytoin or rifampin), prednisone, methylprednisolone, dexamethasone, omeprazole, pantoprazole, esomeprazole, rabeprazole</td>
<td align="left">PO, age, weight (kg), daily dose (mg), CYP2C19inducer (phenytoin or rifampin), prednisone, methylprednisolone, dexamethasone, omeprazole, pantoprazole, esomeprazole, rabeprazole</td>
<td align="left">
<xref ref-type="bibr" rid="B29">Dolton et al. (2012)</xref>
</td>
<td align="left">201 (783)</td>
<td align="left">Adults</td>
<td align="left">0.24</td>
</tr>
<tr>
<td align="left">Age, sex, weight (kg), PO, PPIs, CYP2C19&#x2a;2, CYP2C19&#x2a;17, CYP450 inhibitor combination, CYP450 inductor combination, PPIs, (pantoprazole/omeprazole)</td>
<td align="left">Age</td>
<td align="left">
<xref ref-type="bibr" rid="B30">Dorado et al. (2020)</xref>
</td>
<td align="left">78</td>
<td align="left">Adults</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">ALB (g/dL), CRP (mg/dL), glucocorticoid</td>
<td align="left">ALB (g/dL), CRP (mg/dL), glucocorticoid</td>
<td align="left">
<xref ref-type="bibr" rid="B31">Dote et al. (2016)</xref>
</td>
<td align="left">67 (77)</td>
<td align="left">Patients</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">Age, weight (kg), glucocorticoid, PPIs, CYP2C19&#x2a;2 allele, CYP2C19&#x2a;3 allele</td>
<td align="left">CYP2C19&#x2a;2 allele, CYP2C19&#x2a;3 allele</td>
<td align="left">&#x2a;<xref ref-type="bibr" rid="B35">Fan et al. (2022)</xref>
</td>
<td align="left">68</td>
<td align="left">Pediatric patients</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">Age, weight (kg), PO, sex, PPIs, <xref ref-type="table-fn" rid="Tfn1">
<sup>a</sup>
</xref>CYP2C19 genotype (heterozygous extensive metabolizer, ultrarapid metabolizer, poor metabolizer), glucocorticoids, tacrolimus/cyclosporine, (pantoprazole/omeprazole)</td>
<td align="left">PO, sex, CYP2C19 heterozygous extensive metabolizer (CYP2C19&#x2a;1/&#x2a;2, &#x2a;1/&#x2a;3, &#x2a;2/&#x2a;3, or &#x2a;2/&#x2a;17), CYP2C19 ultrarapid metabolizer (CYP2C19&#x2a;17/&#x2a;17), CYP2C19 poor metabolizer (CYP2C19&#x2a;2/&#x2a;2, &#x2a;3/&#x2a;3), glucocorticoids, PPIs (pantoprazole/omeprazole)</td>
<td align="left">
<xref ref-type="bibr" rid="B39">Hashemizadeh et al. (2017)</xref>
</td>
<td align="left">104 (832)</td>
<td align="left">Adult patients undergoing liver transplant</td>
<td align="left">0.932</td>
</tr>
<tr>
<td align="left">Age, weight (kg), sex, HSCT, IV, PPIs, glucocorticoids, globulin (U/L), ALB (g/L), TBil (&#x3bc;mol/L), DBil (&#x3bc;mol/L), ALT (U/L), AST (U/L), Scr(&#x3bc;mol/L), BUN (mmol/L)</td>
<td align="left">IV, PPIs</td>
<td align="left">
<xref ref-type="bibr" rid="B42">Hu et al. (2018)</xref>
</td>
<td align="left">42 (138)</td>
<td align="left">Pediatric patients</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">Sex, weight (kg), age, IV, ALB (g/L), <xref ref-type="table-fn" rid="Tfn2">
<sup>b</sup>
</xref>CYP2C19 phenotype (intermediate metabolizer, poor metabolizer), omeprazole, glucocorticoids, TBil (&#x3bc;mol/L), ALT (U/L), AST (U/L), Scr(&#x3bc;mol/L), BUN (mmol/L)</td>
<td align="left">CYP2C19 intermediate metabolizer (CYP2C19&#x2a;1/&#x2a;2, &#x2a;1/&#x2a;3), CYP2C19 poor metabolizer (CYP2C19&#x2a;2/&#x2a;2, &#x2a;2/&#x2a;3, or &#x2a;3/&#x2a;3), omeprazole, ALB (g/L), ALT (U/L)</td>
<td align="left">
<xref ref-type="bibr" rid="B44">Hu et al. (2023)</xref>
</td>
<td align="left">131 (250)</td>
<td align="left">Pediatric patients</td>
<td align="left">0.138</td>
</tr>
<tr>
<td align="left">Age (yr.), csevere aplastic anemia, <xref ref-type="table-fn" rid="Tfn2">
<sup>b</sup>
</xref>CYP2C19 phenotype poor metabolizer, PPIs, <xref ref-type="table-fn" rid="Tfn4">
<sup>d</sup>
</xref>poor metabolizer/PPIs user</td>
<td align="left">Age, severe aplastic anemia, CYP2C19 poor metabolizer (CYP2C19&#x2a;2/&#x2a;2, &#x2a;2/&#x2a;3, or &#x2a;3/&#x2a;3), PPIs (omeprazole/lansoprazole/pantoprazole/esomeprazole), CYP2C19 poor metabolizer/PPIs use combination</td>
<td align="left">
<xref ref-type="bibr" rid="B68">Mafuru et al. (2021)</xref>
</td>
<td align="left">114 (250)</td>
<td align="left">Adult patients with hematologic disorders</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">ALB (g/L), ECMO support, corticosteroids</td>
<td align="left">ALB (g/L), ECMO</td>
<td align="left">
<xref ref-type="bibr" rid="B81">Ronda et al. (2023)</xref>
</td>
<td align="left">24 (53)</td>
<td align="left">Adult patients in ICU</td>
<td align="left">&#x2014;</td>
</tr>
<tr>
<td align="left">Obesity status, age, dose (mg/kg), <xref ref-type="table-fn" rid="Tfn5">
<sup>e</sup>
</xref>CYP2C19 phenotype (normal metabolizer, rapid/ultrarapid metabolizer</td>
<td align="left">Obesity status, age, dose (mg/kg), CYP2C19 normal metabolizer (CYP2C19&#x2a;1/&#x2a;1), CYP2C19 rapid (CYP2C19&#x2a;1/&#x2a;17)/ultrarapid metabolizer (CYP2C19&#x2a;17/&#x2a;17)</td>
<td align="left">
<xref ref-type="bibr" rid="B93">Takahashi et al. (2020)</xref>
</td>
<td align="left">44</td>
<td align="left">Children undergoing HSCT</td>
<td align="left">0.33</td>
</tr>
<tr>
<td align="left">Age, PPls non-user, IV, <xref ref-type="table-fn" rid="Tfn5">
<sup>e</sup>
</xref>CYP2C19 phenotype (ultrarapid metabolizer/extensive metabolizers)</td>
<td align="left">Age, CYP2C19 ultrarapid metabolizer (CYP2C19&#x2a;1/&#x2a;17, &#x2a;17/&#x2a;17)/extensive metabolizers (CYP2C19&#x2a;1/&#x2a;1), PPls non-user</td>
<td align="left">
<xref ref-type="bibr" rid="B95">Tian et al. (2021)</xref>
</td>
<td align="left">108 (348)</td>
<td align="left">Children</td>
<td align="left">0.234</td>
</tr>
<tr>
<td align="left">Age, APACHE II, SOFA, Scr(&#x3bc;mol/L), dose (mg), PPIs, glucocorticoids, CRRT, ECMO</td>
<td align="left">Sequential organ failure assessment, dose (mg), glucocorticoids, ECMO</td>
<td align="left">&#x2a;<xref ref-type="bibr" rid="B105">Ye et al. (2022)</xref>
</td>
<td align="left">132 (132)</td>
<td align="left">Adult patients in ICU</td>
<td align="left">0.322</td>
</tr>
<tr>
<td align="left">Loading dose (mg), TBil (&#x3bc;mol/L), PCT (ng/mL), PXRrs3814057</td>
<td align="left">Loading dose (mg), TBil (&#x3bc;mol/L), PCT (ng/mL), PXRrs3814057 polymorphism</td>
<td align="left">
<xref ref-type="bibr" rid="B107">Zeng et al. (2020)</xref>
</td>
<td align="left">170 (510)</td>
<td align="left">Patients with hematological malignancies</td>
<td align="left">0.241</td>
</tr>
<tr>
<td align="left">Daily dose (mg), PTA, sex, <xref ref-type="table-fn" rid="Tfn6">
<sup>f</sup>
</xref>CYP2C19 genotyping (&#x2a;1/&#x2a;2, &#x2a;1/&#x2a;3, &#x2a;2/&#x2a;2)</td>
<td align="left">Daily dose (mg), PTA, sex, CYP2C19 genotyping &#x2a;1/&#x2a;3, CYP2C19 genotyping&#x2a;2/&#x2a;2</td>
<td align="left">
<xref ref-type="bibr" rid="B109">Zhao et al. (2021a)</xref>
</td>
<td align="left">43 (115)</td>
<td align="left">Patient with liver dysfunction</td>
<td align="left">0.348</td>
</tr>
<tr>
<td align="left">Age, ALT (U/L), TBil (&#x3bc;mol/L), ALB (g/L), GGT (U/L)</td>
<td align="left">Age, TBil (&#x3bc;mol/L), GGT (U/L)</td>
<td align="left">
<xref ref-type="bibr" rid="B110">Zhao et al. (2021b)</xref>
</td>
<td align="left">676 (1,212)</td>
<td align="left">Patients</td>
<td align="left">0.270</td>
</tr>
<tr>
<td align="left">Weight (kg), dose (mg/kg), DBil (&#x3bc;mol/L), urea nitrogen, CYP2C19 phenotype (intermediate metabolizer, poor metabolizer)</td>
<td align="left">Weight (kg), dose (mg/kg), DBil (&#x3bc;mol/L), urea nitrogen, CYP2C19 intermediate metabolizer (CYP2C19&#x2a;1/&#x2a;2, &#x2a;1/&#x2a;3 or &#x2a;2/&#x2a;17), CYP2C19 poor metabolizer (CYP2C19&#x2a;2/&#x2a;2, &#x2a;2/&#x2a;3, or &#x2a;3/&#x2a;3)</td>
<td align="left">&#x2a;<xref ref-type="bibr" rid="B111">Zhao Y. C. et al. (2021)</xref>
</td>
<td align="left">94 (145)</td>
<td align="left">Pediatric patients</td>
<td align="left">0.362</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn1">
<label>
<sup>a</sup>
</label>
<p>Compared to homozygous extensive metabolizers (CYP2C19&#x2a;1/&#x2a;1).</p>
</fn>
<fn id="Tfn2">
<label>
<sup>b</sup>
</label>
<p>Compared to normal metabolizer (CYP2C19&#x2a;1/&#x2a;1).</p>
</fn>
<fn id="Tfn3">
<label>
<sup>c</sup>
</label>
<p>Acute myeloid leukemia.</p>
</fn>
<fn id="Tfn4">
<label>
<sup>d</sup>
</label>
<p>Normal metabolizer (CYP2C19&#x2a;1/&#x2a;1)/PPIs, non-user.</p>
</fn>
<fn id="Tfn5">
<label>
<sup>e</sup>
</label>
<p>Compared to poor metabolizers (CYP2C19&#x2a;2/&#x2a;2, &#x2a;2/&#x2a;3, or &#x2a;3/&#x2a;3)/intermediate metabolizers (CYP2C19&#x2a;1/&#x2a;2, &#x2a;1/&#x2a;3, or &#x2a;2/&#x2a;2).</p>
</fn>
<fn id="Tfn6">
<label>
<sup>f</sup>
</label>
<p>CYP2C19 genotyping &#x2a;1/&#x2a;1.</p>
</fn>
<fn>
<p>&#x2a;No &#x3b2;95% CI is given.</p>
</fn>
<fn>
<p>Abbreviations: ALB, albumin; ALT, alanine aminotransferase; PO, per os; AST, aspartate aminotransferase; CRP, C- reactive protein; PPIs, proton pump inhibitors; TBil, total bilirubin; DBil, direct bilirubin; Scr, serum creatinine; BUN, blood urea nitrogen; IV, intravenous; GGT, gamma glutamyl transferase; SOFA, sequential organ failure assessment; PCT, procalcitonin; PTA, prothrombin time activity.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<fig id="F5" position="float">
<label>FIGURE 5</label>
<caption>
<p>Factors associated with voriconazole plasma concentration.</p>
</caption>
<graphic xlink:href="fphar-15-1368274-g005.tif"/>
</fig>
<sec id="s3-5-1">
<title>3.5.1 Age</title>
<p>For the children cohort, among the 21 studies, 6 examined the association between age and voriconazole plasma concentration. However, due to one study did not report the standard error of its coefficient, we pooled the coefficients of only 5 studies. The resulting pooled coefficient was 0.08 (95% CI: 0.01&#x2013;0.14), indicating a statistically significant association. For the adult cohort, 5 of the 20 studies explored the correlation between age and plasma concentration of voriconazole. However, as one study lacked the report of its coefficient&#x2019;s standard error, we combined only the coefficients from 4 studies. The pooled coefficient for this analysis was 0.02 (95% CI: 0.00&#x2013;0.04), but this result was not statistically significant.</p>
</sec>
<sec id="s3-5-2">
<title>3.5.2 Sex</title>
<p>In terms of sex (females), four studies investigated its relationship with voriconazole plasma concentration in children. The relationship between sex (females) and voriconazole plasma concentration in adults was examined in two studies. We pooled the coefficients and standard errors from the children and adults, respectively. The pooled coefficients for this analysis were &#x2212;0.16 (95% CI: &#x2212;0.46 to 0.14) for children and &#x2212;0.08 (95% CI: &#x2212;0.44 to 0.28) for adults, but these results were not statistically significant.</p>
</sec>
<sec id="s3-5-3">
<title>3.5.3 Weight</title>
<p>In the children cohort and the adult cohort, respectively, three studies reported both coefficients and standard errors from multiple linear regression analyses. When these coefficients and standard errors were pooled separately, the resulting coefficients were &#x2212;0.01 (95% CI: &#x2212;0.05 to 0.02) for children and &#x2212;0.01 (95% CI: &#x2212;0.03 to 0.01) for adult, both of which lacked statistical significance.</p>
</sec>
<sec id="s3-5-4">
<title>3.5.4 Voriconazole dose</title>
<p>The voriconazole doses administered to adults and children varied, requiring separate pooling of the adult dose, the dose for children, and their respective plasma concentrations. The pooled coefficients for dose (mg) and dose (mg/kg) were 0.01 (95% CI: 0.00&#x2013;0.02) and 0.23 (95% CI: &#x2212;0.15 to 0.62), neither of which was statistically significant.</p>
</sec>
<sec id="s3-5-5">
<title>3.5.5 Route of administration</title>
<p>This study investigated the correlation between plasma voriconazole concentration and intravenous administration in children, as well as the correlation with oral administration in adults. The pooled coefficients for these were &#x2212;0.02 (95% CI: &#x2212;0.58 to 0.80) and &#x2212;0.72 (95% CI: &#x2212;1.63 to 0.19), respectively, with no statistical significance observed in either case.</p>
</sec>
<sec id="s3-5-6">
<title>3.5.6 Albumin</title>
<p>Only two studies confirmed the relationship between albumin and voriconazole plasma concentration in children. The pooled coefficient was &#x2212;0.05 (95% CI: &#x2212;0.09 to &#x2212;0.01), indicating a statistically significant association.</p>
</sec>
<sec id="s3-5-7">
<title>3.5.7 Liver function</title>
<p>Several indicators of liver function were considered, but the study focused on the correlations between TBil, ALT, AST, and voriconazole concentration in children. The pooled coefficients for these indicators were 0.17 (95% CI: &#x2212;0.30 to 0.65), 0.00 (95% CI: &#x2212;0.01 to 0.00), and 0.01 (95% CI: 0.00&#x2013;0.01), respectively. However, none showed statistically significant correlations.</p>
</sec>
<sec id="s3-5-8">
<title>3.5.8 Drug combinations</title>
<p>Three studies explored the correlation between PPIs and voriconazole plasma concentration in adults, but the pooled estimate did not show statistical significance. For specific PPIs, two studies focused on omeprazole in relation to voriconazole plasma concentration in adults, and another two on pantoprazole in relation to voriconazole plasma concentration in adults. The pooled coefficients were 1.37 (95% CI 0.82&#x2013;1.92) for omeprazole and 1.11 (95% CI: 0.17&#x2013;2.04) for pantoprazole. These results suggest that omeprazole and pantoprazole increase voriconazole plasma concentration by 1.37-fold and 1.11-fold, respectively.</p>
<p>Two studies on glucocorticoids were pooled to assess their association with plasma voriconazole concentration in children. The pooled coefficient was &#x2212;0.51 (95% CI: &#x2212;1.66 to 2.67). Three studies on glucocorticoids were pooled to assess their association with plasma voriconazole concentration in adults. The pooled coefficient was &#x2212;1.33 (95% CI: &#x2212;3.25 to 0.58). But the results all did not show statistical significance. Two studies focused on methylprednisolone in correlation to voriconazole plasma concentration in adults, and another two on dexamethasone in correlation to voriconazole plasma concentration in adults. The pooled coefficients were &#x2212;1.75 (95% CI: &#x2212;2.21 to &#x2212;1.30) for methylprednisolone and &#x2212;1.45 (95% CI: &#x2212;2.07 to &#x2212;0.83) for dexamethasone, indicating that the voriconazole plasma concentration decreased by 1.75-fold and 1.45-fold, respectively, with the concurrent use of these glucocorticoids in adults.</p>
</sec>
<sec id="s3-5-9">
<title>3.5.9 Inflammation and genetic factor</title>
<p>Only one study established a correlation between C-reactive protein (CRP) and plasma voriconazole concentration; therefore, we did not pool the coefficient and standard error for this parameter. Among the 20 studies, 11 reported a correlation between the CYP2C19 genotype or phenotype and plasma voriconazole concentration. However, the coefficients and standard errors of these studies were not pooled.</p>
</sec>
</sec>
<sec id="s3-6">
<title>3.6 Publication bias</title>
<p>We used the Egger test, the Begg test, and the trim-and-fill method to assess publication bias in the pooled estimate of the prevalence of patients reaching the therapeutic range of plasma voriconazole concentration. Begg&#x2019;s test yielded a result of 0.127, and Egger&#x2019;s test showed 0.045. Although the Egger test result did not exceed the threshold of 0.05, it was close to this limit. Consequently, the trim-and-fill method was applied to further the analysis. Using the linear method with two iterations, the software estimated that no studies were missing, suggesting an absence of publication bias. The detailed results of the trim-and-fill method are presented in in <xref ref-type="sec" rid="s11">Supplementary Figure S2</xref>.</p>
</sec>
</sec>
<sec sec-type="discussion" id="s4">
<title>4 Discussion</title>
<p>The high pharmacokinetic variability of voriconazole and the benefits of maintaining its&#x2019; plasma concentration within the therapeutic range to improve efficacy and safety are well recognized. This study represents the first effort to pool data on the prevalence of patients who achieve this therapeutic range, underscoring the vital importance of TDM in voriconazole. Our analysis of the factors that influence plasma voriconazole concentration offers valuable evidence to healthcare decision-makers, helping to develop more effective voriconazole treatment strategies.</p>
<p>In the studies included in our analysis, the prevalence of patients reaching the therapeutic range of voriconazole plasma concentration varied widely, ranging from 33% to 84%. This variance can be partly attributed to the recommended therapeutic range of voriconazole plasma concentration varies in different regions. For example, guidelines in Japan, the United Kingdom, Australia, and the United States typically recommend a range of 1.0&#x2013;5.5&#xa0;mg/L for voriconazole (<xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>; <xref ref-type="bibr" rid="B38">Hamada et al., 2013</xref>; <xref ref-type="bibr" rid="B74">Pappas et al., 2016</xref>; <xref ref-type="bibr" rid="B13">Chau et al., 2021</xref>), while the Canadian guideline suggests 1.5&#x2013;5.0&#xa0;mg/L (<xref ref-type="bibr" rid="B56">Laverdiere et al., 2014</xref>), and in China, it is defined as 0.5&#x2013;5.5&#xa0;mg/L (<xref ref-type="bibr" rid="B17">Chen et al., 2018</xref>). Our study included studies that adopted nine different therapeutic ranges for plasma voriconazole concentration. Although the therapeutic range, sex, and the analytical method for voriconazole measurement were identified as significant factors affecting heterogeneity through meta-regression, other contributors could not be completely excluded. These may include variations in treatment duration, types of treatment settings, and the purpose of voriconazole use (prophylaxis or treatment), all of which could influence achieving the effective and safe therapeutic concentration. Additionally, disparities in study design and patient populations might also affect the prevalence of patients reaching the effective and safe therapeutic range of voriconazole concentrations.</p>
<p>The pooled prevalence was higher in studies with dose adjustments in accordance with TDM and guidelines than in studies without dose adjustments. The results suggested that dose adjustment according to TDM and guidelines is helpful to improve the prevalence of patients reaching concentrations within the effective and safe range. Since most of the studies were retrospective, many of them only mentioned the CYP2C19 genotype testing, but did not mention whether the dose was adjusted according to the genotype. This prevented us from determining the effect of dose adjustment based on CYP2C19 genotype on patients achieving therapeutic range. After subgroup analysis according to the study population, the pooled prevalence of adult patients reaching the therapeutic range is higher than that of children. In adults, the physiological maturity and stability facilitate achieving the effective and safe therapeutic range of voriconazole plasma concentration. In contrast, children exhibit a lower prevalence of reaching the target concentration due to the incomplete development of their metabolic enzyme systems, variations in drug distribution and absorption, and greater individual physiological variability.</p>
<p>Numerous factors influence plasma voriconazole concentration, as highlighted in our study, which included 21 studies that performed multiple linear regression analyses to explore these relationships. Factors associated with plasma voriconazole concentration identified in the literature included primarily demographic characteristics (age, sex, weight, ethnicity, etc.), genetic factors (such as CYP2C19 gene polymorphism), drug interactions (with PPIs, glucocorticoids, etc.), administration methods (oral, intravenous), and dosage. However, not all of these factors were found to have a significant correlation with plasma voriconazole concentration. Although our study did not pool coefficients and standard errors between the CYP2C19 genotype or phenotype and voriconazole plasma concentration, the impact of CYP2C19 on voriconazole plasma concentration is well established. A clinical study has shown that the plasma concentration of voriconazole is influenced by CYP2C19 genotype in both children and adults (<xref ref-type="bibr" rid="B44">Hu et al., 2023</xref>). CYP2C19 is crucial in voriconazole metabolism and exhibits a significant genetic polymorphism (<xref ref-type="bibr" rid="B27">Dean, 2012</xref>). Poor metabolizers show an approximately four-fold increase in voriconazole exposure compared to homozygous normal metabolizers (<xref ref-type="bibr" rid="B27">Dean, 2012</xref>). Heterozygous normal metabolizers experience, on average, a two-fold increase in exposure compared to their homozygous normal counterparts (<xref ref-type="bibr" rid="B27">Dean, 2012</xref>). Single nucleotide polymorphisms (SNPs) in the CYP2C19 gene account for approximately 50%&#x2013;55% of variability in voriconazole metabolism (<xref ref-type="bibr" rid="B72">Murayama et al., 2007</xref>). Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DWPG) recommend adjusting the voriconazole dosing regimen based on the CYP2C19 genotype (<xref ref-type="bibr" rid="B71">Moriyama et al., 2017</xref>; <xref ref-type="bibr" rid="B92">Swen et al., 2011</xref>). Therefore, it is recommended that both adults and children should adjust the voriconazole dosing regimen based on CYP2C19 genotype.</p>
<p>We observed a weak correlation between age and voriconazole plasma concentration in children, but not in adults. This difference may be attributed to differences in drug metabolism and physiological characteristics between the two groups. Moreover, since children&#x2019;s physiological and metabolic systems are not fully developed, their response to medication may change as they age. A systematic review showed that the dosing of voriconazole in pediatric patients was age-dependent, with younger children requiring higher doses to reach target concentration compared to older children (<xref ref-type="bibr" rid="B43">Hu et al., 2024</xref>).</p>
<p>Several studies have highlighted the impact of inflammation on voriconazole metabolism (<xref ref-type="bibr" rid="B63">Liang et al., 2022</xref>; <xref ref-type="bibr" rid="B9">Bolcato et al., 2021</xref>). Inflammatory cytokines, such as IL-6 and IL-8, can modulate drug-metabolizing enzymes and transporters (DMETs) (<xref ref-type="bibr" rid="B90">Stanke-Labesque et al., 2020</xref>), affecting the expression of CYP2C19 and CYP34A, influencing voriconazole plasma concentration (<xref ref-type="bibr" rid="B100">Vreugdenhil et al., 2018</xref>; <xref ref-type="bibr" rid="B36">Gautier-Veyret et al., 2017</xref>; <xref ref-type="bibr" rid="B53">Klein et al., 2015</xref>; <xref ref-type="bibr" rid="B58">Li et al., 2014</xref>). CRP, an inflammation indicator, was shown to influence the plasma concentration of voriconazole by impacting CYP2C19 activity (<xref ref-type="bibr" rid="B99">Van Wanrooy et al., 2014</xref>; <xref ref-type="bibr" rid="B82">Ruiz et al., 2019</xref>; <xref ref-type="bibr" rid="B88">Simon et al., 2021</xref>). However, our analysis was limited by the small number of studies addressing CPR, IL-6, and IL-8. Consequently, we could not pool the coefficients from multiple linear regressions for a random-effects model. A systematic review indicated that the level of inflammation (CRP levels) can significantly affect voriconazole plasma concentration in adults (<xref ref-type="bibr" rid="B60">Li et al., 2022</xref>). However, a clinical study identified variations in the correlation between CRP levels and voriconazole plasma concentration among pediatric patients across different age groups (<xref ref-type="bibr" rid="B67">Luo et al., 2021</xref>). The impact of inflammation (CRP levels) on voriconazole metabolism in children should need further analysis in relation to age groups, which requires a further exploration with a larger sample size.</p>
<p>In our analysis, we found a weak correlation between albumin and voriconazole plasma concentrations in children. Regarding the correlation between albumin and plasma concentration of voriconazole in adults, this article could not conduct research, but some studies showed that hypoproteinemia affected the plasma concentration of voriconazole in adults (<xref ref-type="bibr" rid="B62">Li et al., 2023</xref>; <xref ref-type="bibr" rid="B12">Chantharit et al., 2020</xref>; <xref ref-type="bibr" rid="B51">Khan-Asa et al., 2020</xref>). The inflammatory cytokine IL-6 increased CRP synthesis and decreased albumin synthesis in the liver (<xref ref-type="bibr" rid="B10">Bologa et al., 1998</xref>), likely leading to higher voriconazole plasma concentrations due to elevated CRP levels rather than reduced albumin.</p>
<p>Voriconazole is predominantly metabolized in the liver through oxidative processes mediated by CYP450 enzymes, including CYP2C19, CYP3A4, and CYP2C9 (<xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>). Liver injury may cause metabolic abnormalities and increased exposure, affecting plasma voriconazole concentration. Hepatocellular injury is often indicated by elevated levels of ALT and AST (<xref ref-type="bibr" rid="B55">Kwo et al., 2017</xref>). Due to the exclusion of patients with abnormal liver function in some included studies and the limited number of studies that conducted multiple linear regression to assess correlations between AST, ALT, Child-Pugh class, and plasma voriconazole concentration, our study did not observe a definitive correlation between these liver function indicators and plasma voriconazole concentration in the children and adult population. However, we recommend dose reduction or avoidance of voriconazole in patients with impaired liver function (<xref ref-type="bibr" rid="B38">Hamada et al., 2013</xref>; <xref ref-type="bibr" rid="B64">Limper et al., 2011</xref>). The Japanese guideline (<xref ref-type="bibr" rid="B38">Hamada et al., 2013</xref>) recommends maintaining the loading dose but halving the maintenance dose for patients with severe liver disease classified as Child-Pugh classes A and B, while voriconazole is not recommended for those in class C. Similarly, United Kingdom, Canada, the United States, and Australia guidelines generally do not recommend antifungal therapy for patients with severe liver insufficiency (<xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>; <xref ref-type="bibr" rid="B56">Laverdiere et al., 2014</xref>; <xref ref-type="bibr" rid="B13">Chau et al., 2021</xref>; <xref ref-type="bibr" rid="B74">Pappas et al., 2016</xref>). The Chinese guideline (<xref ref-type="bibr" rid="B17">Chen et al., 2018</xref>) advises against using voriconazole as an initial therapy for patients with severe liver disease, recommending close monitoring of plasma concentration and liver function if its use is deemed necessary.</p>
<p>The correlation between plasma voriconazole concentration and PPIs in adults were not found in our study, however, we found that voriconazole plasma concentration was positively correlated with omeprazole and pantoprazole in adults. Additionally, we also did not observe the relationship between plasma voriconazole concentration and glucocorticoids in children and adults, however, a negatively correlated between methylprednisolone, dexamethasone and voriconazole plasma concentration in adults was found in our study. Voriconazole inhibits the activity of CYP2C19, CYP3A4, and CYP2C9, resulting in several clinically significant drug interactions (<xref ref-type="bibr" rid="B3">Ashbee et al., 2014</xref>). PPIs(<xref ref-type="bibr" rid="B54">Klotz et al., 2004</xref>; <xref ref-type="bibr" rid="B61">Li et al., 2004</xref>) and glucocorticoids (<xref ref-type="bibr" rid="B26">Czock et al., 2005</xref>; <xref ref-type="bibr" rid="B21">Chen et al., 2003</xref>) are known to affect CYP2C19 activity. However, neither PPIs nor glucocorticoids seem to affect the pharmacokinetics of voriconazole (<xref ref-type="bibr" rid="B87">Shi et al., 2019</xref>). Some studies indicated that glucocorticoids and PPIs can impact plasma voriconazole concentration (<xref ref-type="bibr" rid="B48">Jia et al., 2021</xref>; <xref ref-type="bibr" rid="B61">Li et al., 2004</xref>). Rabeprazole and lansoprazole are less potent CYP450 inhibitors compared to omeprazole and pantoprazole (<xref ref-type="bibr" rid="B61">Li et al., 2004</xref>), and another study found that voriconazole plasma concentration decreased significantly with dexamethasone or methylprednisolone, but less so with prednisone or prednisolone (<xref ref-type="bibr" rid="B48">Jia et al., 2021</xref>). Our analysis did not find a correlation between the PPIs as a group, glucocorticoids as a group and plasma voriconazole concentration, possibly due to the inclusion of different types of PPIs and glucocorticoids in the reviewed studies. In summary, the effects of PPIs and glucocorticoids on voriconazole pharmacokinetics are disputed. Indeed, substantial studies showed that the type of PPI and dose (or glucocorticoid) significantly impact on voriconazole exposure (<xref ref-type="bibr" rid="B78">Qi et al., 2017</xref>; <xref ref-type="bibr" rid="B48">Jia et al., 2021</xref>). Drug interactions may occur in both adults and children; thus, attention should be paid to the combined use of glucocorticoids or PPIs, including consideration of the type and dose of these medications.</p>
<p>Although our study provides a comprehensive quantitative summary of the prevalence of patients who achieve the therapeutic range of plasma voriconazole concentration and associated factors, it is important to recognize several limitations. First, the included studies covered a global scale, including various medical practices, economic conditions, geographic locations, and cultural backgrounds. These factors could influence the reported prevalence of patients who reached the therapeutic voriconazole concentration. Second, the studies exhibited high heterogeneity, possibly due to variations in sample size, study populations, sex distribution, indications for voriconazole use, dose adjustments, and concentration measurement methodologies. Third, the restriction to studies published in English might have led to an underestimation or overestimation of prevalence and limited the pooling of several factors. Some factors in our study were only analyzed in two studies, raising concerns about possible bias in these results. Therefore, further research is warranted to better understand the factors associated with voriconazole plasma concentration.</p>
</sec>
<sec sec-type="conclusion" id="s5">
<title>5 Conclusion</title>
<p>The analysis revealed that only approximately half of the patients reached the plasma voriconazole concentration therapeutic range without dose adjustments and the pooled prevalence of adult patients reaching the therapeutic range is higher than that of children. The meta-analysis identified factors associated with voriconazole plasma concentration in children, including age, albumin levels. Meanwhile, it also identified the factors related to plasma voriconazole concentration in adults, including the use of omeprazole, pantoprazole, dexamethasone and methylprednisolone.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="s6">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="sec" rid="s11">Supplementary Material</xref>, further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s7">
<title>Author contributions</title>
<p>XL: Writing&#x2013;original draft. QH: Writing&#x2013;original draft. TX: Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s8">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by National Key Clinical Specialties Construction Program.</p>
</sec>
<sec sec-type="COI-statement" id="s9">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s10">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s11">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fphar.2024.1368274/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fphar.2024.1368274/full&#x23;supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="DataSheet1.docx" id="SM1" mimetype="application/docx" xmlns:xlink="http://www.w3.org/1999/xlink"/>
</sec>
<ref-list>
<title>References</title>
<ref id="B1">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Aiuchi</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Nakagawa</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Sakuraba</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Takahata</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Kamata</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Saito</surname>
<given-names>N.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Impact of polymorphisms of pharmacokinetics-related genes and the inflammatory response on the metabolism of voriconazole</article-title>. <source>Pharmacol. Res. and Perspect.</source> <volume>10</volume>, <fpage>11</fpage>. <pub-id pub-id-type="doi">10.1002/prp2.935</pub-id>
</citation>
</ref>
<ref id="B2">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Allegra</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Fatiguso</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Francia</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Pirro</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Carcieri</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Cusato</surname>
<given-names>J.</given-names>
</name>
<etal/>
</person-group> (<year>2018</year>). <article-title>Pharmacogenetic of voriconazole antifungal agent in pediatric patients</article-title>. <source>Pharmacogenomics</source> <volume>19</volume>, <fpage>913</fpage>&#x2013;<lpage>925</lpage>. <pub-id pub-id-type="doi">10.2217/pgs-2017-0173</pub-id>
</citation>
</ref>
<ref id="B3">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ashbee</surname>
<given-names>H. R.</given-names>
</name>
<name>
<surname>Barnes</surname>
<given-names>R. A.</given-names>
</name>
<name>
<surname>Johnson</surname>
<given-names>E. M.</given-names>
</name>
<name>
<surname>Richardson</surname>
<given-names>M. D.</given-names>
</name>
<name>
<surname>Gorton</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Hope</surname>
<given-names>W. W.</given-names>
</name>
</person-group> (<year>2014</year>). <article-title>Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology</article-title>. <source>J. Antimicrob. Chemother.</source> <volume>69</volume>, <fpage>1162</fpage>&#x2013;<lpage>1176</lpage>. <pub-id pub-id-type="doi">10.1093/jac/dkt508</pub-id>
</citation>
</ref>
<ref id="B4">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bartelink</surname>
<given-names>I. H.</given-names>
</name>
<name>
<surname>Wolfs</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Jonker</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>De Waal</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Egberts</surname>
<given-names>T. C.</given-names>
</name>
<name>
<surname>Ververs</surname>
<given-names>T. T.</given-names>
</name>
<etal/>
</person-group> (<year>2013</year>). <article-title>Highly variable plasma concentrations of voriconazole in pediatric hematopoietic stem cell transplantation patients</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>57</volume>, <fpage>235</fpage>&#x2013;<lpage>240</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.01540-12</pub-id>
</citation>
</ref>
<ref id="B5">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Benedict</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Gold</surname>
<given-names>J. A. W.</given-names>
</name>
<name>
<surname>Toda</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Thompson</surname>
<given-names>G. R.</given-names>
</name>
<name>
<surname>Wiederhold</surname>
<given-names>N. P.</given-names>
</name>
<name>
<surname>Smith</surname>
<given-names>D. J.</given-names>
</name>
</person-group> (<year>2023</year>). <article-title>Low rates of antifungal therapeutic drug monitoring among inpatients who received itraconazole, posaconazole, or voriconazole, United States, 2019-2021</article-title>. <source>Open Forum Infect. Dis.</source> <volume>10</volume>, <fpage>ofad389</fpage>. <pub-id pub-id-type="doi">10.1093/ofid/ofad389</pub-id>
</citation>
</ref>
<ref id="B6">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Blanco-Dorado</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Cea-Arestin</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Gonzalez Carballo</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Latorre-Pellicer</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Maronas Amigo</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>Barbeito Castineiras</surname>
<given-names>G.</given-names>
</name>
<etal/>
</person-group> (<year>2019</year>). <article-title>An observational study of the efficacy and safety of voriconazole in a real-life clinical setting</article-title>. <source>J. Chemother.</source> <volume>31</volume> (<issue>1</issue>), <fpage>49</fpage>&#x2013;<lpage>57</lpage>. <pub-id pub-id-type="doi">10.1080/1120009X.2018.1524085</pub-id>
</citation>
</ref>
<ref id="B7">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Blanco-Dorado</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Maro&#xf1;as</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>Latorre-Pellicer</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Rodr&#xed;guez Jato</surname>
<given-names>M. T.</given-names>
</name>
<name>
<surname>L&#xf3;pez-Vizca&#xed;no</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>G&#xf3;mez M&#xe1;rquez</surname>
<given-names>A.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Impact of CYP2C19 genotype and drug interactions on voriconazole plasma concentrations: a Spain pharmacogenetic-pharmacokinetic prospective multicenter study</article-title>. <source>Pharmacotherapy</source> <volume>40</volume>, <fpage>17</fpage>&#x2013;<lpage>25</lpage>. <pub-id pub-id-type="doi">10.1002/phar.2351</pub-id>
</citation>
</ref>
<ref id="B8">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Boast</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Curtis</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Cranswick</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Gwee</surname>
<given-names>A.</given-names>
</name>
</person-group> (<year>2016</year>). <article-title>Voriconazole dosing and therapeutic drug monitoring in children: experience from a paediatric tertiary care centre</article-title>. <source>J. Antimicrob. Chemother.</source> <volume>71</volume>, <fpage>2031</fpage>&#x2013;<lpage>2036</lpage>. <pub-id pub-id-type="doi">10.1093/jac/dkw056</pub-id>
</citation>
</ref>
<ref id="B9">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bolcato</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Khouri</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Veringa</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Alffenaar</surname>
<given-names>J. W. C.</given-names>
</name>
<name>
<surname>Yamada</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Naito</surname>
<given-names>T.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Combined impact of inflammation and pharmacogenomic variants on voriconazole trough concentrations: a meta-analysis of individual data</article-title>. <source>J. Clin. Med.</source> <volume>10</volume>, <fpage>2089</fpage>. <pub-id pub-id-type="doi">10.3390/jcm10102089</pub-id>
</citation>
</ref>
<ref id="B10">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bologa</surname>
<given-names>R. M.</given-names>
</name>
<name>
<surname>Levine</surname>
<given-names>D. M.</given-names>
</name>
<name>
<surname>Parker</surname>
<given-names>T. S.</given-names>
</name>
<name>
<surname>Cheigh</surname>
<given-names>J. S.</given-names>
</name>
<name>
<surname>Serur</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Stenzel</surname>
<given-names>K. H.</given-names>
</name>
<etal/>
</person-group> (<year>1998</year>). <article-title>Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients</article-title>. <source>Am. J. Kidney Dis.</source> <volume>32</volume>, <fpage>107</fpage>&#x2013;<lpage>114</lpage>. <pub-id pub-id-type="doi">10.1053/ajkd.1998.v32.pm9669431</pub-id>
</citation>
</ref>
<ref id="B11">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cabral-Galeano</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Ruiz-Camps</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Len-Abad</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>Pou-Clav&#xe9;</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Sord&#xe9;-Masip</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Meije-Castillo</surname>
<given-names>Y.</given-names>
</name>
<etal/>
</person-group> (<year>2015</year>). <article-title>Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital</article-title>. <source>Enferm. Infecc. Microbiol. Clin.</source> <volume>33</volume>, <fpage>298</fpage>&#x2013;<lpage>302</lpage>. <pub-id pub-id-type="doi">10.1016/j.eimc.2014.09.005</pub-id>
</citation>
</ref>
<ref id="B12">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chantharit</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Tantasawat</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Kasai</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Tanigawara</surname>
<given-names>Y.</given-names>
</name>
</person-group> (<year>2020</year>). <article-title>Population pharmacokinetics of voriconazole in patients with invasive aspergillosis: serum albumin level as a novel marker for clearance and dosage optimization</article-title>. <source>Ther. Drug Monit.</source> <volume>42</volume>, <fpage>872</fpage>&#x2013;<lpage>879</lpage>. <pub-id pub-id-type="doi">10.1097/FTD.0000000000000799</pub-id>
</citation>
</ref>
<ref id="B13">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chau</surname>
<given-names>M. M.</given-names>
</name>
<name>
<surname>Daveson</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Alffenaar</surname>
<given-names>J. C.</given-names>
</name>
<name>
<surname>Gwee</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Ho</surname>
<given-names>S. A.</given-names>
</name>
<name>
<surname>Marriott</surname>
<given-names>D. J. E.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021</article-title>. <source>Intern Med. J.</source> <volume>51</volume> (<issue>Suppl. 7</issue>), <fpage>37</fpage>&#x2013;<lpage>66</lpage>. <pub-id pub-id-type="doi">10.1111/imj.15587</pub-id>
</citation>
</ref>
<ref id="B14">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chaudhri</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Stocker</surname>
<given-names>S. L.</given-names>
</name>
<name>
<surname>Williams</surname>
<given-names>K. M.</given-names>
</name>
<name>
<surname>Mcleay</surname>
<given-names>R. C.</given-names>
</name>
<name>
<surname>Marriott</surname>
<given-names>D. J. E.</given-names>
</name>
<name>
<surname>Di Tanna</surname>
<given-names>G. L.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Voriconazole: an audit of hospital-based dosing and monitoring and evaluation of the predictive performance of a dose-prediction software package</article-title>. <source>J. Antimicrob. Chemother.</source> <volume>75</volume>, <fpage>1981</fpage>&#x2013;<lpage>1984</lpage>. <pub-id pub-id-type="doi">10.1093/jac/dkaa098</pub-id>
</citation>
</ref>
<ref id="B15">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>C. Y.</given-names>
</name>
<name>
<surname>Xu</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Zhou</surname>
<given-names>K. T.</given-names>
</name>
<name>
<surname>Zhu</surname>
<given-names>S. Y.</given-names>
</name>
</person-group> (<year>2022</year>). <article-title>Factors affecting voriconazole concentration to dose ratio changes according to route of administration</article-title>. <source>Eur. J. Hosp. Pharm.</source> <volume>5</volume>. <pub-id pub-id-type="doi">10.1136/ejhpharm-2021-003173</pub-id>
</citation>
</ref>
<ref id="B16">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>He</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Feng</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Ren</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>S.</given-names>
</name>
</person-group> (<year>2022</year>). <article-title>Combined effect of CYP2C19 genetic polymorphisms and C-reactive protein on voriconazole exposure and dosing in immunocompromised children</article-title>. <source>Front. Pediatr.</source> <volume>10</volume>. <pub-id pub-id-type="doi">10.3389/fped.2022.846411</pub-id>
</citation>
</ref>
<ref id="B17">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Ke</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Du</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Zhai</surname>
<given-names>S.</given-names>
</name>
</person-group> (<year>2018</year>). <article-title>Individualized medication of voriconazole: a practice guideline of the division of therapeutic drug monitoring, Chinese pharmacological society</article-title>. <source>Ther. Drug Monit.</source> <volume>40</volume>, <fpage>663</fpage>&#x2013;<lpage>674</lpage>. <pub-id pub-id-type="doi">10.1097/FTD.0000000000000561</pub-id>
</citation>
</ref>
<ref id="B18">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>T. T.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>S. F.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>H. T.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>Q. Q.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>Z. Q.</given-names>
</name>
</person-group> (<year>2022</year>). <article-title>Therapeutic drug monitoring of voriconazole in AIDS patients</article-title>. <source>Lat. Am. J. Pharm.</source> <volume>41</volume>, <fpage>2020</fpage>&#x2013;<lpage>2026</lpage>. <pub-id pub-id-type="doi">10.21203/rs.3.rs-1010995/v1</pub-id>
</citation>
</ref>
<ref id="B19">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>W. Q.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>X. X.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Qin</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>X. X.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Effects of voriconazole exposure on the pharmacokinetics of tacrolimus in lung transplantation patients, based on therapeutic drug monitoring data</article-title>. <source>J. Clin. Pharmacol.</source> <volume>62</volume>, <fpage>1310</fpage>&#x2013;<lpage>1320</lpage>. <pub-id pub-id-type="doi">10.1002/jcph.2066</pub-id>
</citation>
</ref>
<ref id="B20">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Gao</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>X.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Therapeutic drug monitoring and CYP2C19 genotyping guide the application of voriconazole in children</article-title>. <source>Transl. Pediatr.</source> <volume>11</volume> (<issue>8</issue>), <fpage>1311</fpage>&#x2013;<lpage>1322</lpage>. <pub-id pub-id-type="doi">10.21037/tp-22-156</pub-id>
</citation>
</ref>
<ref id="B21">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Ferguson</surname>
<given-names>S. S.</given-names>
</name>
<name>
<surname>Negishi</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Goldstein</surname>
<given-names>J. A.</given-names>
</name>
</person-group> (<year>2003</year>). <article-title>Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter</article-title>. <source>Mol. Pharmacol.</source> <volume>64</volume>, <fpage>316</fpage>&#x2013;<lpage>324</lpage>. <pub-id pub-id-type="doi">10.1124/mol.64.2.316</pub-id>
</citation>
</ref>
<ref id="B22">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cheng</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Xiang</surname>
<given-names>R. F.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>Y. L.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>H. L.</given-names>
</name>
<name>
<surname>Yao</surname>
<given-names>P.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Therapeutic drug monitoring and safety of voriconazole in elderly patients</article-title>. <source>Int. Immunopharmacol.</source> <volume>78</volume>, <fpage>106078</fpage>. <pub-id pub-id-type="doi">10.1016/j.intimp.2019.106078</pub-id>
</citation>
</ref>
<ref id="B23">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Choi</surname>
<given-names>S. H.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>S. Y.</given-names>
</name>
<name>
<surname>Hwang</surname>
<given-names>J. Y.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>S. H.</given-names>
</name>
<name>
<surname>Yoo</surname>
<given-names>K. H.</given-names>
</name>
<name>
<surname>Sung</surname>
<given-names>K. W.</given-names>
</name>
<etal/>
</person-group> (<year>2013</year>). <article-title>Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis</article-title>. <source>Pediatr. Blood Cancer</source> <volume>60</volume>, <fpage>82</fpage>&#x2013;<lpage>87</lpage>. <pub-id pub-id-type="doi">10.1002/pbc.24262</pub-id>
</citation>
</ref>
<ref id="B24">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chuwongwattana</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Jantararoungtong</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Chitasombat</surname>
<given-names>M. N.</given-names>
</name>
<name>
<surname>Puangpetch</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Prommas</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Dilokpattanamongkol</surname>
<given-names>P.</given-names>
</name>
<etal/>
</person-group> (<year>2016</year>). <article-title>A prospective observational study of CYP2C19 polymorphisms and voriconazole plasma level in adult Thai patients with invasive aspergillosis</article-title>. <source>Drug Metab. Pharmacokinet.</source> <volume>31</volume>, <fpage>117</fpage>&#x2013;<lpage>122</lpage>. <pub-id pub-id-type="doi">10.1016/j.dmpk.2015.12.005</pub-id>
</citation>
</ref>
<ref id="B25">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cojutti</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Candoni</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Forghieri</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Isola</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Zannier</surname>
<given-names>M. E.</given-names>
</name>
<name>
<surname>Bigliardi</surname>
<given-names>S.</given-names>
</name>
<etal/>
</person-group> (<year>2016</year>). <article-title>Variability of voriconazole trough levels in haematological patients: influence of comedications with cytochrome P450(CYP) inhibitors and/or with CYP inhibitors plus CYP inducers</article-title>. <source>Basic Clin. Pharmacol. Toxicol.</source> <volume>118</volume>, <fpage>474</fpage>&#x2013;<lpage>479</lpage>. <pub-id pub-id-type="doi">10.1111/bcpt.12530</pub-id>
</citation>
</ref>
<ref id="B26">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Czock</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Keller</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Rasche</surname>
<given-names>F. M.</given-names>
</name>
<name>
<surname>H&#xe4;ussler</surname>
<given-names>U.</given-names>
</name>
</person-group> (<year>2005</year>). <article-title>Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids</article-title>. <source>Clin. Pharmacokinet.</source> <volume>44</volume>, <fpage>61</fpage>&#x2013;<lpage>98</lpage>. <pub-id pub-id-type="doi">10.2165/00003088-200544010-00003</pub-id>
</citation>
</ref>
<ref id="B27">
<citation citation-type="book">
<person-group person-group-type="author">
<name>
<surname>Dean</surname>
<given-names>L.</given-names>
</name>
</person-group> (<year>2012</year>). &#x201c;<article-title>Voriconazole therapy and CYP2C19 genotype</article-title>,&#x201d; in <source>Medical genetics summaries</source>. Editors <person-group person-group-type="editor">
<name>
<surname>Pratt</surname>
<given-names>V. M.</given-names>
</name>
<name>
<surname>Scott</surname>
<given-names>S. A.</given-names>
</name>
<name>
<surname>Pirmohamed</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Esquivel</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Kattman</surname>
<given-names>B. L.</given-names>
</name>
<name>
<surname>Malheiro</surname>
<given-names>A. J.</given-names>
</name>
</person-group> (<publisher-loc>Bethesda (MD)</publisher-loc>: <publisher-name>National Center for Biotechnology Information</publisher-name>).</citation>
</ref>
<ref id="B28">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Dolton</surname>
<given-names>M. J.</given-names>
</name>
<name>
<surname>Mclachlan</surname>
<given-names>A. J.</given-names>
</name>
</person-group> (<year>2014</year>). <article-title>Voriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity</article-title>. <source>Int. J. Antimicrob. Agents</source> <volume>44</volume>, <fpage>183</fpage>&#x2013;<lpage>193</lpage>. <pub-id pub-id-type="doi">10.1016/j.ijantimicag.2014.05.019</pub-id>
</citation>
</ref>
<ref id="B29">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Dolton</surname>
<given-names>M. J.</given-names>
</name>
<name>
<surname>Ray</surname>
<given-names>J. E.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>S. C. A.</given-names>
</name>
<name>
<surname>Ng</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Pont</surname>
<given-names>L. G.</given-names>
</name>
<name>
<surname>Mclachlan</surname>
<given-names>A. J.</given-names>
</name>
</person-group> (<year>2012</year>). <article-title>Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>56</volume>, <fpage>4793</fpage>&#x2013;<lpage>4799</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.00626-12</pub-id>
</citation>
</ref>
<ref id="B30">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Dorado</surname>
<given-names>S. B.</given-names>
</name>
<name>
<surname>Amigo</surname>
<given-names>O. M.</given-names>
</name>
<name>
<surname>Latorre-Pellicer</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Jato</surname>
<given-names>M. T. R.</given-names>
</name>
<name>
<surname>Lopez-Vizcaino</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Marquez</surname>
<given-names>A. G.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations</article-title>. <source>Br. J. Clin. Pharmacol.</source> <volume>86</volume>, <fpage>1661</fpage>&#x2013;<lpage>1666</lpage>. <pub-id pub-id-type="doi">10.1111/bcp.14267</pub-id>
</citation>
</ref>
<ref id="B31">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Dote</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Sawai</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Nozaki</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Naruhashi</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Kobayashi</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Nakanishi</surname>
<given-names>H.</given-names>
</name>
</person-group> (<year>2016</year>). <article-title>A retrospective analysis of patient-specific factors on voriconazole clearance</article-title>. <source>J. Pharm. Health Care Sci.</source> <volume>2</volume> (<issue>1</issue>), <fpage>10</fpage>. <pub-id pub-id-type="doi">10.1186/s40780-016-0044-9</pub-id>
</citation>
</ref>
<ref id="B32">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Duehlmeyer</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Klockau</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Yu</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Rouch</surname>
<given-names>J.</given-names>
</name>
</person-group> (<year>2021</year>). <article-title>Characterization of therapeutic drug monitoring practices of voriconazole and posaconazole at a pediatric hospital</article-title>. <source>J. Pediatr. Pharmacol. Ther.</source> <volume>26</volume> (<issue>1</issue>), <fpage>26</fpage>&#x2013;<lpage>32</lpage>. <pub-id pub-id-type="doi">10.5863/1551-6776-26.1.26</pub-id>
</citation>
</ref>
<ref id="B33">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ebrahimpour</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Namazi</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Mohammadi</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Nikbakht</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Hadjibabaie</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Masoumi</surname>
<given-names>H.</given-names>
</name>
<etal/>
</person-group> (<year>2017</year>). <article-title>Impact of CYP2C19 polymorphisms on serum concentration of voriconazole in iranian hematological patients</article-title>. <source>J. Res. Pharm. Pract.</source> <volume>6</volume> (<issue>3</issue>), <fpage>151</fpage>&#x2013;<lpage>157</lpage>. <pub-id pub-id-type="doi">10.4103/jrpp.JRPP_17_31</pub-id>
</citation>
</ref>
<ref id="B34">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Elewa</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>El-Mekaty</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>El-Bardissy</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Ensom</surname>
<given-names>M. H.</given-names>
</name>
<name>
<surname>Wilby</surname>
<given-names>K. J.</given-names>
</name>
</person-group> (<year>2015</year>). <article-title>Therapeutic drug monitoring of voriconazole in the management of invasive fungal infections: a critical review</article-title>. <source>Clin. Pharmacokinet.</source> <volume>54</volume>, <fpage>1223</fpage>&#x2013;<lpage>1235</lpage>. <pub-id pub-id-type="doi">10.1007/s40262-015-0297-8</pub-id>
</citation>
</ref>
<ref id="B35">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Fan</surname>
<given-names>X. H.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Wen</surname>
<given-names>Z. P.</given-names>
</name>
<name>
<surname>Zheng</surname>
<given-names>X. L.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>J. H.</given-names>
</name>
</person-group> (<year>2022</year>). <article-title>Effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole levels in Chinese pediatric patients</article-title>. <source>Pharmacogenetics Genomics</source> <volume>32</volume>, <fpage>152</fpage>&#x2013;<lpage>158</lpage>. <pub-id pub-id-type="doi">10.1097/FPC.0000000000000464</pub-id>
</citation>
</ref>
<ref id="B36">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Gautier-Veyret</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Bailly</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Fonrose</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Tonini</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Chevalier</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Thiebaut-Bertrand</surname>
<given-names>A.</given-names>
</name>
<etal/>
</person-group> (<year>2017</year>). <article-title>Pharmacogenetics may influence the impact of inflammation on voriconazole trough concentrations</article-title>. <source>Pharmacogenomics</source> <volume>18</volume>, <fpage>1119</fpage>&#x2013;<lpage>1123</lpage>. <pub-id pub-id-type="doi">10.2217/pgs-2017-0054</pub-id>
</citation>
</ref>
<ref id="B37">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hamada</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Seto</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Yago</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Kuroyama</surname>
<given-names>M.</given-names>
</name>
</person-group> (<year>2012</year>). <article-title>Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis</article-title>. <source>J. Infect. Chemother.</source> <volume>18</volume>, <fpage>501</fpage>&#x2013;<lpage>507</lpage>. <pub-id pub-id-type="doi">10.1007/s10156-011-0363-6</pub-id>
</citation>
</ref>
<ref id="B38">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hamada</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Tokimatsu</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Mikamo</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Kimura</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Seki</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Takakura</surname>
<given-names>S.</given-names>
</name>
<etal/>
</person-group> (<year>2013</year>). <article-title>Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring</article-title>. <source>J. Infect. Chemother.</source> <volume>19</volume>, <fpage>381</fpage>&#x2013;<lpage>392</lpage>. <pub-id pub-id-type="doi">10.1007/s10156-013-0607-8</pub-id>
</citation>
</ref>
<ref id="B39">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hashemizadeh</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Badiee</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Malekhoseini</surname>
<given-names>S. A.</given-names>
</name>
<name>
<surname>Shahraki</surname>
<given-names>H. R.</given-names>
</name>
<name>
<surname>Geramizadeh</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Montaseri</surname>
<given-names>H.</given-names>
</name>
</person-group> (<year>2017</year>). <article-title>Observational study of associations between voriconazole therapeutic drug monitoring, toxicity, and outcome in liver transplant patients</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>61</volume>, <fpage>e01211</fpage>&#x2013;<lpage>17</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.01211-17</pub-id>
</citation>
</ref>
<ref id="B40">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hoenigl</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Duettmann</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Raggam</surname>
<given-names>R. B.</given-names>
</name>
<name>
<surname>Seeber</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Troppan</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Fruhwald</surname>
<given-names>S.</given-names>
</name>
<etal/>
</person-group> (<year>2013</year>). <article-title>Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>57</volume>, <fpage>3262</fpage>&#x2013;<lpage>3267</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.00251-13</pub-id>
</citation>
</ref>
<ref id="B41">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hope</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Natarajan</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Goodwin</surname>
<given-names>L.</given-names>
</name>
</person-group> (<year>2013</year>). <article-title>Invasive fungal infections</article-title>. <source>Clin. Med. (Lond)</source> <volume>13</volume>, <fpage>507</fpage>&#x2013;<lpage>510</lpage>. <pub-id pub-id-type="doi">10.7861/clinmedicine.13-5-507</pub-id>
</citation>
</ref>
<ref id="B42">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Dai</surname>
<given-names>T. T.</given-names>
</name>
<name>
<surname>Zou</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>T. M.</given-names>
</name>
<name>
<surname>Ding</surname>
<given-names>X. S.</given-names>
</name>
<name>
<surname>Yin</surname>
<given-names>T.</given-names>
</name>
</person-group> (<year>2018</year>). <article-title>Therapeutic drug monitoring of voriconazole in children from a tertiary care center in China</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>62</volume>, <fpage>e00955</fpage>&#x2013;<lpage>18</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.00955-18</pub-id>
</citation>
</ref>
<ref id="B43">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>He</surname>
<given-names>G.</given-names>
</name>
</person-group> (<year>2024</year>). <article-title>Clinical application of voriconazole in pediatric patients: a systematic review</article-title>. <source>Ital. J. Pediatr.</source> <volume>50</volume>, <fpage>113</fpage>. <pub-id pub-id-type="doi">10.1186/s13052-024-01684-z</pub-id>
</citation>
</ref>
<ref id="B44">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Feng</surname>
<given-names>Z.</given-names>
</name>
</person-group> (<year>2023</year>). <article-title>Therapeutic drug monitoring of voriconazole and CYP2C19 phenotype for dose optimization in paediatric patients</article-title>. <source>Eur. J. Clin. Pharmacol.</source> <volume>79</volume>, <fpage>1271</fpage>&#x2013;<lpage>1278</lpage>. <pub-id pub-id-type="doi">10.1007/s00228-023-03538-9</pub-id>
</citation>
</ref>
<ref id="B45">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Huang</surname>
<given-names>H. G.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>H. L.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>Y. K.</given-names>
</name>
<name>
<surname>Yi</surname>
<given-names>Y. D.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Dong</surname>
<given-names>J. L.</given-names>
</name>
<etal/>
</person-group> (<year>2023</year>). <article-title>Factors influencing and adverse reactions of voriconazole clearance in patients with hematological diseases</article-title>. <source>Zhongguo Shi Yan Xue Ye Xue Za Zhi</source> <volume>31</volume>, <fpage>562</fpage>&#x2013;<lpage>567</lpage>. <pub-id pub-id-type="doi">10.19746/j.cnki.issn.1009-2137.2023.02.036</pub-id>
</citation>
</ref>
<ref id="B46">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Huang</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Yin</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Hu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Ding</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>S.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Effect of proton pump inhibitors on voriconazole concentrations in Chinese patients with malignant hematological diseases</article-title>. <source>Eur. J. Clin. Pharmacol.</source> <volume>76</volume>, <fpage>833</fpage>&#x2013;<lpage>842</lpage>. <pub-id pub-id-type="doi">10.1007/s00228-020-02841-z</pub-id>
</citation>
</ref>
<ref id="B47">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jeans</surname>
<given-names>A. R.</given-names>
</name>
<name>
<surname>Howard</surname>
<given-names>S. J.</given-names>
</name>
<name>
<surname>Al-Nakeeb</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Goodwin</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Gregson</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Warn</surname>
<given-names>P. A.</given-names>
</name>
<etal/>
</person-group> (<year>2012</year>). <article-title>Combination of voriconazole and anidulafungin for treatment of triazole-resistant aspergillus fumigatus in an <italic>in vitro</italic> model of invasive pulmonary aspergillosis</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>56</volume>, <fpage>5180</fpage>&#x2013;<lpage>5185</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.01111-12</pub-id>
</citation>
</ref>
<ref id="B48">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jia</surname>
<given-names>S. J.</given-names>
</name>
<name>
<surname>Gao</surname>
<given-names>K. Q.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>P. H.</given-names>
</name>
<name>
<surname>Guo</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Zuo</surname>
<given-names>X. C.</given-names>
</name>
<name>
<surname>Xia</surname>
<given-names>Q.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Interactive effects of glucocorticoids and cytochrome P450 polymorphisms on the plasma trough concentrations of voriconazole</article-title>. <source>Front. Pharmacol.</source> <volume>12</volume>, <fpage>666296</fpage>. <pub-id pub-id-type="doi">10.3389/fphar.2021.666296</pub-id>
</citation>
</ref>
<ref id="B49">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jin</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Falcione</surname>
<given-names>B. A.</given-names>
</name>
<name>
<surname>Olsen</surname>
<given-names>K. M.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Tang</surname>
<given-names>H.</given-names>
</name>
<etal/>
</person-group> (<year>2016</year>). <article-title>Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis</article-title>. <source>J. Antimicrob. Chemother.</source> <volume>71</volume>, <fpage>1772</fpage>&#x2013;<lpage>1785</lpage>. <pub-id pub-id-type="doi">10.1093/jac/dkw045</pub-id>
</citation>
</ref>
<ref id="B50">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kang</surname>
<given-names>H. M.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>H. J.</given-names>
</name>
<name>
<surname>Cho</surname>
<given-names>E. Y.</given-names>
</name>
<name>
<surname>Yu</surname>
<given-names>K. S.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>J. W.</given-names>
</name>
<etal/>
</person-group> (<year>2015</year>). <article-title>The clinical significance of voriconazole therapeutic drug monitoring in children with invasive fungal infections</article-title>. <source>Pediatr. Hematol. Oncol.</source> <volume>32</volume>, <fpage>557</fpage>&#x2013;<lpage>567</lpage>. <pub-id pub-id-type="doi">10.3109/08880018.2015.1088905</pub-id>
</citation>
</ref>
<ref id="B51">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Khan-Asa</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Punyawudho</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Singkham</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Chaivichacharn</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Karoopongse</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Montakantikul</surname>
<given-names>P.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Impact of albumin and omeprazole on steady-state population pharmacokinetics of voriconazole and development of a voriconazole dosing optimization model in Thai patients with hematologic diseases</article-title>. <source>Antibiot. (Basel)</source> <volume>9</volume>, <fpage>574</fpage>. <pub-id pub-id-type="doi">10.3390/antibiotics9090574</pub-id>
</citation>
</ref>
<ref id="B52">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kim</surname>
<given-names>D. Y.</given-names>
</name>
<name>
<surname>Park</surname>
<given-names>H. J.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>Y. J.</given-names>
</name>
</person-group> (<year>2014</year>). <article-title>Factors affecting voriconazole plasma concentrations in patients with invasive fungal infections</article-title>. <source>Int. J. Clin. Pharmacol. Ther.</source> <volume>52</volume>, <fpage>209</fpage>&#x2013;<lpage>216</lpage>. <pub-id pub-id-type="doi">10.5414/CP202014</pub-id>
</citation>
</ref>
<ref id="B53">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Klein</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Thomas</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Hofmann</surname>
<given-names>U.</given-names>
</name>
<name>
<surname>Seehofer</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Damm</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Zanger</surname>
<given-names>U. M.</given-names>
</name>
</person-group> (<year>2015</year>). <article-title>A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells</article-title>. <source>Drug Metab. Dispos.</source> <volume>43</volume>, <fpage>273</fpage>&#x2013;<lpage>283</lpage>. <pub-id pub-id-type="doi">10.1124/dmd.114.060962</pub-id>
</citation>
</ref>
<ref id="B54">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Klotz</surname>
<given-names>U.</given-names>
</name>
<name>
<surname>Schwab</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Treiber</surname>
<given-names>G.</given-names>
</name>
</person-group> (<year>2004</year>). <article-title>CYP2C19 polymorphism and proton pump inhibitors</article-title>. <source>Basic Clin. Pharmacol. Toxicol.</source> <volume>95</volume>, <fpage>2</fpage>&#x2013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1111/j.1600-0773.2004.pto950102.x</pub-id>
</citation>
</ref>
<ref id="B55">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kwo</surname>
<given-names>P. Y.</given-names>
</name>
<name>
<surname>Cohen</surname>
<given-names>S. M.</given-names>
</name>
<name>
<surname>Lim</surname>
<given-names>J. K.</given-names>
</name>
</person-group> (<year>2017</year>). <article-title>ACG clinical guideline: evaluation of abnormal liver chemistries</article-title>. <source>Am. J. Gastroenterol.</source> <volume>112</volume>, <fpage>18</fpage>&#x2013;<lpage>35</lpage>. <pub-id pub-id-type="doi">10.1038/ajg.2016.517</pub-id>
</citation>
</ref>
<ref id="B56">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Laverdiere</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Bow</surname>
<given-names>E. J.</given-names>
</name>
<name>
<surname>Rotstein</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Autmizguine</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Broady</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Garber</surname>
<given-names>G.</given-names>
</name>
<etal/>
</person-group> (<year>2014</year>). <article-title>Therapeutic drug monitoring for triazoles: a needs assessment review and recommendations from a Canadian perspective</article-title>. <source>Can. J. Infect. Dis. Med. Microbiol.</source> <volume>25</volume>, <fpage>327</fpage>&#x2013;<lpage>343</lpage>. <pub-id pub-id-type="doi">10.1155/2014/340586</pub-id>
</citation>
</ref>
<ref id="B57">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Lempers</surname>
<given-names>V. J.</given-names>
</name>
<name>
<surname>Meuwese</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Mavinkurve-Groothuis</surname>
<given-names>A. M.</given-names>
</name>
<name>
<surname>Henriet</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Van Der Sluis</surname>
<given-names>I. M.</given-names>
</name>
<name>
<surname>Hanff</surname>
<given-names>L. M.</given-names>
</name>
<etal/>
</person-group> (<year>2019</year>). <article-title>Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients</article-title>. <source>Med. Mycol.</source> <volume>57</volume>, <fpage>937</fpage>&#x2013;<lpage>943</lpage>. <pub-id pub-id-type="doi">10.1093/mmy/myz006</pub-id>
</citation>
</ref>
<ref id="B58">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname>
<given-names>A. P.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Vermet</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Raoust</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Klieber</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Fabre</surname>
<given-names>G.</given-names>
</name>
</person-group> (<year>2014</year>). <article-title>Evaluation of human hepatocytes under prolonged culture in a novel medium for the maintenance of hepatic differentiation: results with the model pro-inflammatory cytokine interleukin 6</article-title>. <source>Drug Metab. Lett.</source> <volume>8</volume>, <fpage>12</fpage>&#x2013;<lpage>18</lpage>. <pub-id pub-id-type="doi">10.2174/187231280801140929155351</pub-id>
</citation>
</ref>
<ref id="B59">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Yan</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Gao</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Zhou</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>Y.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Voriconazole therapeutic drug monitoring in critically ill patients improves efficacy and safety of antifungal therapy</article-title>. <source>Basic Clin. Pharmacol. Toxicol.</source> <volume>127</volume>, <fpage>495</fpage>&#x2013;<lpage>504</lpage>. <pub-id pub-id-type="doi">10.1111/bcpt.13465</pub-id>
</citation>
</ref>
<ref id="B60">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Lai</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Jiang</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>J.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Effects of inflammation on voriconazole levels: a systematic review</article-title>. <source>Br. J. Clin. Pharmacol.</source> <volume>88</volume>, <fpage>5166</fpage>&#x2013;<lpage>5182</lpage>. <pub-id pub-id-type="doi">10.1111/bcp.15495</pub-id>
</citation>
</ref>
<ref id="B61">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname>
<given-names>X. Q.</given-names>
</name>
<name>
<surname>Andersson</surname>
<given-names>T. B.</given-names>
</name>
<name>
<surname>Ahlstr&#xf6;m</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Weidolf</surname>
<given-names>L.</given-names>
</name>
</person-group> (<year>2004</year>). <article-title>Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities</article-title>. <source>Drug Metab. Dispos.</source> <volume>32</volume>, <fpage>821</fpage>&#x2013;<lpage>827</lpage>. <pub-id pub-id-type="doi">10.1124/dmd.32.8.821</pub-id>
</citation>
</ref>
<ref id="B62">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname>
<given-names>Y. Y.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Zhao</surname>
<given-names>J. X.</given-names>
</name>
<name>
<surname>Bian</surname>
<given-names>J. L.</given-names>
</name>
<name>
<surname>Zhao</surname>
<given-names>Y. Y.</given-names>
</name>
<name>
<surname>Hao</surname>
<given-names>X.</given-names>
</name>
<etal/>
</person-group> (<year>2023</year>). <article-title>Combined impact of hypoalbuminemia and pharmacogenomic variants on voriconazole trough concentration: data from a real-life clinical setting in the Chinese population</article-title>. <source>J. Chemother.</source> <volume>11</volume>. <pub-id pub-id-type="doi">10.1080/1120009x.2023.2247208</pub-id>
</citation>
</ref>
<ref id="B63">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Liang</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Yu</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Jia</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Xiong</surname>
<given-names>L.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Inflammation affects liver function and the metabolism of voriconazole to voriconazole-N-oxide in adult and elderly patients</article-title>. <source>Front. Pharmacol.</source> <volume>13</volume>, <fpage>835871</fpage>. <pub-id pub-id-type="doi">10.3389/fphar.2022.835871</pub-id>
</citation>
</ref>
<ref id="B64">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Limper</surname>
<given-names>A. H.</given-names>
</name>
<name>
<surname>Knox</surname>
<given-names>K. S.</given-names>
</name>
<name>
<surname>Sarosi</surname>
<given-names>G. A.</given-names>
</name>
<name>
<surname>Ampel</surname>
<given-names>N. M.</given-names>
</name>
<name>
<surname>Bennett</surname>
<given-names>J. E.</given-names>
</name>
<name>
<surname>Catanzaro</surname>
<given-names>A.</given-names>
</name>
<etal/>
</person-group> (<year>2011</year>). <article-title>An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients</article-title>. <source>Am. J. Respir. Crit. Care Med.</source> <volume>183</volume>, <fpage>96</fpage>&#x2013;<lpage>128</lpage>. <pub-id pub-id-type="doi">10.1164/rccm.2008-740ST</pub-id>
</citation>
</ref>
<ref id="B65">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Liu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Zhou</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Jiang</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>Y.</given-names>
</name>
</person-group> (<year>2017</year>). <article-title>Dose optimisation of voriconazole with therapeutic drug monitoring in children: a single-centre experience in China</article-title>. <source>Int. J. Antimicrob. Agents</source> <volume>49</volume>, <fpage>483</fpage>&#x2013;<lpage>487</lpage>. <pub-id pub-id-type="doi">10.1016/j.ijantimicag.2016.11.028</pub-id>
</citation>
</ref>
<ref id="B66">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ludden</surname>
<given-names>T. M.</given-names>
</name>
</person-group> (<year>1991</year>). <article-title>Nonlinear pharmacokinetics: clinical Implications</article-title>. <source>Clin. Pharmacokinet.</source> <volume>20</volume>, <fpage>429</fpage>&#x2013;<lpage>446</lpage>. <pub-id pub-id-type="doi">10.2165/00003088-199120060-00001</pub-id>
</citation>
</ref>
<ref id="B67">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Luo</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Hu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Zhao</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>J.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Differential effects of C-reactive protein levels on voriconazole metabolism at three age groups in allogeneic hematopoietic cell transplant recipients</article-title>. <source>J. Chemother.</source> <volume>33</volume>, <fpage>95</fpage>&#x2013;<lpage>105</lpage>. <pub-id pub-id-type="doi">10.1080/1120009X.2020.1765604</pub-id>
</citation>
</ref>
<ref id="B68">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mafuru</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>S. L.</given-names>
</name>
<name>
<surname>Mayala</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Msengwa</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Phillip</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Mgone</surname>
<given-names>C.</given-names>
</name>
</person-group> (<year>2021</year>). <article-title>Analysis of combined effect of CYP2C19 genetic polymorphism and proton pump inhibitors coadministration on trough concentration of voriconazole</article-title>. <source>Pharmacogenomics and Personalized Med.</source> <volume>14</volume>, <fpage>1379</fpage>&#x2013;<lpage>1389</lpage>. <pub-id pub-id-type="doi">10.2147/PGPM.S329662</pub-id>
</citation>
</ref>
<ref id="B69">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Miao</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Tang</surname>
<given-names>J. T.</given-names>
</name>
<name>
<surname>Van Gelder</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>Y. M.</given-names>
</name>
<name>
<surname>Bai</surname>
<given-names>Y. J.</given-names>
</name>
<name>
<surname>Zou</surname>
<given-names>Y. G.</given-names>
</name>
<etal/>
</person-group> (<year>2019</year>). <article-title>Correlation of CYP2C19 genotype with plasma voriconazole exposure in South-western Chinese Han patients with invasive fungal infections</article-title>. <source>Med. Baltim.</source> <volume>98</volume>, <fpage>e14137</fpage>. <pub-id pub-id-type="doi">10.1097/MD.0000000000014137</pub-id>
</citation>
</ref>
<ref id="B70">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Moher</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Shamseer</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Clarke</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Ghersi</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Liberati</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Petticrew</surname>
<given-names>M.</given-names>
</name>
<etal/>
</person-group> (<year>2015</year>). <article-title>Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement</article-title>. <source>Syst. Rev.</source> <volume>4</volume>, <fpage>1</fpage>. <pub-id pub-id-type="doi">10.1186/2046-4053-4-1</pub-id>
</citation>
</ref>
<ref id="B71">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Moriyama</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Obeng</surname>
<given-names>A. O.</given-names>
</name>
<name>
<surname>Barbarino</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Penzak</surname>
<given-names>S. R.</given-names>
</name>
<name>
<surname>Henning</surname>
<given-names>S. A.</given-names>
</name>
<name>
<surname>Scott</surname>
<given-names>S. A.</given-names>
</name>
<etal/>
</person-group> (<year>2017</year>). <article-title>Clinical Pharmacogenetics implementation Consortium (CPIC) guidelines for CYP2C19 and voriconazole therapy</article-title>. <source>Clin. Pharmacol. Ther.</source> <volume>102</volume>, <fpage>45</fpage>&#x2013;<lpage>51</lpage>. <pub-id pub-id-type="doi">10.1002/cpt.583</pub-id>
</citation>
</ref>
<ref id="B72">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Murayama</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Imai</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Nakane</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Shimizu</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Yamazaki</surname>
<given-names>H.</given-names>
</name>
</person-group> (<year>2007</year>). <article-title>Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes</article-title>. <source>Biochem. Pharmacol.</source> <volume>73</volume>, <fpage>2020</fpage>&#x2013;<lpage>2026</lpage>. <pub-id pub-id-type="doi">10.1016/j.bcp.2007.03.012</pub-id>
</citation>
</ref>
<ref id="B73">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Myrianthefs</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Markantonis</surname>
<given-names>S. L.</given-names>
</name>
<name>
<surname>Evaggelopoulou</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Despotelis</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Evodia</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Panidis</surname>
<given-names>D.</given-names>
</name>
<etal/>
</person-group> (<year>2010</year>). <article-title>Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study</article-title>. <source>Int. J. Antimicrob. Agents</source> <volume>35</volume>, <fpage>468</fpage>&#x2013;<lpage>472</lpage>. <pub-id pub-id-type="doi">10.1016/j.ijantimicag.2009.12.021</pub-id>
</citation>
</ref>
<ref id="B74">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pappas</surname>
<given-names>P. G.</given-names>
</name>
<name>
<surname>Kauffman</surname>
<given-names>C. A.</given-names>
</name>
<name>
<surname>Andes</surname>
<given-names>D. R.</given-names>
</name>
<name>
<surname>Clancy</surname>
<given-names>C. J.</given-names>
</name>
<name>
<surname>Marr</surname>
<given-names>K. A.</given-names>
</name>
<name>
<surname>Ostrosky-Zeichner</surname>
<given-names>L.</given-names>
</name>
<etal/>
</person-group> (<year>2016</year>). <article-title>Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America</article-title>. <source>Clin. Infect. Dis.</source> <volume>62</volume>, <fpage>e1</fpage>&#x2013;<lpage>e50</lpage>. <pub-id pub-id-type="doi">10.1093/cid/civ933</pub-id>
</citation>
</ref>
<ref id="B75">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Park</surname>
<given-names>W. B.</given-names>
</name>
<name>
<surname>Kim</surname>
<given-names>N. H.</given-names>
</name>
<name>
<surname>Kim</surname>
<given-names>K. H.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>S. H.</given-names>
</name>
<name>
<surname>Nam</surname>
<given-names>W. S.</given-names>
</name>
<name>
<surname>Yoon</surname>
<given-names>S. H.</given-names>
</name>
<etal/>
</person-group> (<year>2012</year>). <article-title>The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial</article-title>. <source>Clin. Infect. Dis.</source> <volume>55</volume>, <fpage>1080</fpage>&#x2013;<lpage>1087</lpage>. <pub-id pub-id-type="doi">10.1093/cid/cis599</pub-id>
</citation>
</ref>
<ref id="B76">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Patterson</surname>
<given-names>T. F.</given-names>
</name>
<name>
<surname>Thompson</surname>
<given-names>G. R. 3rd</given-names>
</name>
<name>
<surname>Denning</surname>
<given-names>D. W.</given-names>
</name>
<name>
<surname>Fishman</surname>
<given-names>J. A.</given-names>
</name>
<name>
<surname>Hadley</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Herbrecht</surname>
<given-names>R.</given-names>
</name>
<etal/>
</person-group> (<year>2016</year>). <article-title>Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America</article-title>. <source>Clin. Infect. Dis.</source> <volume>63</volume>, <fpage>e1</fpage>&#x2013;<lpage>e60</lpage>. <pub-id pub-id-type="doi">10.1093/cid/ciw326</pub-id>
</citation>
</ref>
<ref id="B77">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pieper</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Kolve</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Gumbinger</surname>
<given-names>H. G.</given-names>
</name>
<name>
<surname>Goletz</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Wurthwein</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Groll</surname>
<given-names>A. H.</given-names>
</name>
</person-group> (<year>2012</year>). <article-title>Monitoring of voriconazole plasma concentrations in immunocompromised paediatric patients</article-title>. <source>J. Antimicrob. Chemother.</source> <volume>67</volume>, <fpage>2717</fpage>&#x2013;<lpage>2724</lpage>. <pub-id pub-id-type="doi">10.1093/jac/dks258</pub-id>
</citation>
</ref>
<ref id="B78">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Qi</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Zhu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Ge</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Xu</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Liao</surname>
<given-names>S.</given-names>
</name>
</person-group> (<year>2017</year>). <article-title>Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole</article-title>. <source>Int. J. Antimicrob. Agents</source> <volume>49</volume>, <fpage>403</fpage>&#x2013;<lpage>409</lpage>. <pub-id pub-id-type="doi">10.1016/j.ijantimicag.2016.11.025</pub-id>
</citation>
</ref>
<ref id="B79">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Resztak</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Sobiak</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Czyrski</surname>
<given-names>A.</given-names>
</name>
</person-group> (<year>2021</year>). <article-title>Recent advances in therapeutic drug monitoring of voriconazole, mycophenolic acid, and vancomycin: a literature review of pediatric studies</article-title>. <source>Pharmaceutics</source> <volume>13</volume>, <fpage>1991</fpage>. <pub-id pub-id-type="doi">10.3390/pharmaceutics13121991</pub-id>
</citation>
</ref>
<ref id="B80">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rolden</surname>
<given-names>H. J.</given-names>
</name>
<name>
<surname>Van Bodegom</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Van Den Hout</surname>
<given-names>W. B.</given-names>
</name>
<name>
<surname>Westendorp</surname>
<given-names>R. G.</given-names>
</name>
</person-group> (<year>2014</year>). <article-title>Old age mortality and macroeconomic cycles</article-title>. <source>J. Epidemiol. Community Health</source> <volume>68</volume>, <fpage>44</fpage>&#x2013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1136/jech-2013-202544</pub-id>
</citation>
</ref>
<ref id="B81">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ronda</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Llop-Talaveron</surname>
<given-names>J. M.</given-names>
</name>
<name>
<surname>Fuset</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Leiva</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Shaw</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Gumucio-Sanguino</surname>
<given-names>V. D.</given-names>
</name>
<etal/>
</person-group> (<year>2023</year>). <article-title>Voriconazole pharmacokinetics in critically ill patients and extracorporeal membrane oxygenation support: a retrospective comparative case-control study</article-title>. <source>Antibiotics-Basel</source> <volume>12</volume>, <fpage>1100</fpage>. <pub-id pub-id-type="doi">10.3390/antibiotics12071100</pub-id>
</citation>
</ref>
<ref id="B82">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ruiz</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Gordon</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Villarreal</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Peruccioni</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Marques</surname>
<given-names>M. R.</given-names>
</name>
<name>
<surname>Poveda-Andres</surname>
<given-names>J. L.</given-names>
</name>
<etal/>
</person-group> (<year>2019</year>). <article-title>Impact of voriconazole plasma concentrations on treatment response in critically ill patients</article-title>. <source>J. Clin. Pharm. Ther.</source> <volume>44</volume>, <fpage>572</fpage>&#x2013;<lpage>578</lpage>. <pub-id pub-id-type="doi">10.1111/jcpt.12817</pub-id>
</citation>
</ref>
<ref id="B83">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sabatelli</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Patel</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Mann</surname>
<given-names>P. A.</given-names>
</name>
<name>
<surname>Mendrick</surname>
<given-names>C. A.</given-names>
</name>
<name>
<surname>Norris</surname>
<given-names>C. C.</given-names>
</name>
<name>
<surname>Hare</surname>
<given-names>R.</given-names>
</name>
<etal/>
</person-group> (<year>2006</year>). <article-title>
<italic>In vitro</italic> activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>50</volume>, <fpage>2009</fpage>&#x2013;<lpage>2015</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.00163-06</pub-id>
</citation>
</ref>
<ref id="B84">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Saini</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Seki</surname>
<given-names>J. T.</given-names>
</name>
<name>
<surname>Kumar</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Atenafu</surname>
<given-names>E. G.</given-names>
</name>
<name>
<surname>Cole</surname>
<given-names>D. E. C.</given-names>
</name>
<name>
<surname>Wong</surname>
<given-names>B. Y. L.</given-names>
</name>
<etal/>
</person-group> (<year>2014</year>). <article-title>Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy</article-title>. <source>Can. J. Infect. Dis. and Med. Microbiol.</source> <volume>25</volume>, <fpage>271</fpage>&#x2013;<lpage>276</lpage>. <pub-id pub-id-type="doi">10.1155/2014/214813</pub-id>
</citation>
</ref>
<ref id="B85">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shao</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Ma</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Zhu</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Zhao</surname>
<given-names>H.</given-names>
</name>
<etal/>
</person-group> (<year>2017</year>). <article-title>Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes</article-title>. <source>Xenobiotica</source> <volume>47</volume> (<issue>12</issue>), <fpage>1121</fpage>&#x2013;<lpage>1129</lpage>. <pub-id pub-id-type="doi">10.1080/00498254.2016.1271960</pub-id>
</citation>
</ref>
<ref id="B86">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shen</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Gu</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Lu</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Ni</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Zhong</surname>
<given-names>H.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Therapeutic drug monitoring and safety evaluation of voriconazole in the treatment of pulmonary fungal diseases</article-title>. <source>Ther. Adv. Drug Saf.</source> <volume>13</volume>, <fpage>20420986221127503</fpage>. <pub-id pub-id-type="doi">10.1177/20420986221127503</pub-id>
</citation>
</ref>
<ref id="B87">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shi</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Mao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>N.</given-names>
</name>
</person-group> (<year>2019</year>). <article-title>Voriconazole: a review of population pharmacokinetic analyses</article-title>. <source>Clin. Pharmacokinet.</source> <volume>58</volume>, <fpage>687</fpage>&#x2013;<lpage>703</lpage>. <pub-id pub-id-type="doi">10.1007/s40262-019-00735-7</pub-id>
</citation>
</ref>
<ref id="B88">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Simon</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Gautier-Veyret</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Truffot</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Chenel</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Payen</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Stanke-Labesque</surname>
<given-names>F.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Modeling approach to predict the impact of inflammation on the pharmacokinetics of CYP2C19 and CYP3A4 substrates</article-title>. <source>Pharm. Res.</source> <volume>38</volume>, <fpage>415</fpage>&#x2013;<lpage>428</lpage>. <pub-id pub-id-type="doi">10.1007/s11095-021-03019-7</pub-id>
</citation>
</ref>
<ref id="B89">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Soler-Palacin</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Frick</surname>
<given-names>M. A.</given-names>
</name>
<name>
<surname>Martin-Nalda</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Lanaspa</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Pou</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Rosello</surname>
<given-names>E.</given-names>
</name>
<etal/>
</person-group> (<year>2012</year>). <article-title>Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study</article-title>. <source>J. Antimicrob. Chemother.</source> <volume>67</volume>, <fpage>700</fpage>&#x2013;<lpage>706</lpage>. <pub-id pub-id-type="doi">10.1093/jac/dkr517</pub-id>
</citation>
</ref>
<ref id="B90">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Stanke-Labesque</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Gautier-Veyret</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Chhun</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Guilhaumou</surname>
<given-names>R.</given-names>
</name>
</person-group> (<year>2020</year>). <article-title>Inflammation is a major regulator of drug metabolizing enzymes and transporters: consequences for the personalization of drug treatment</article-title>. <source>Pharmacol. Ther.</source> <volume>215</volume>, <fpage>107627</fpage>. <pub-id pub-id-type="doi">10.1016/j.pharmthera.2020.107627</pub-id>
</citation>
</ref>
<ref id="B91">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Stroup</surname>
<given-names>D. F.</given-names>
</name>
<name>
<surname>Berlin</surname>
<given-names>J. A.</given-names>
</name>
<name>
<surname>Morton</surname>
<given-names>S. C.</given-names>
</name>
<name>
<surname>Olkin</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Williamson</surname>
<given-names>G. D.</given-names>
</name>
<name>
<surname>Rennie</surname>
<given-names>D.</given-names>
</name>
<etal/>
</person-group> (<year>2000</year>). <article-title>Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group</article-title>. <source>Jama</source> <volume>283</volume>, <fpage>2008</fpage>&#x2013;<lpage>2012</lpage>. <pub-id pub-id-type="doi">10.1001/jama.283.15.2008</pub-id>
</citation>
</ref>
<ref id="B92">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Swen</surname>
<given-names>J. J.</given-names>
</name>
<name>
<surname>Nijenhuis</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>De Boer</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Grandia</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Maitland-Van Der Zee</surname>
<given-names>A. H.</given-names>
</name>
<name>
<surname>Mulder</surname>
<given-names>H.</given-names>
</name>
<etal/>
</person-group> (<year>2011</year>). <article-title>Pharmacogenetics: from bench to byte--an update of guidelines</article-title>. <source>Clin. Pharmacol. Ther.</source> <volume>89</volume>, <fpage>662</fpage>&#x2013;<lpage>673</lpage>. <pub-id pub-id-type="doi">10.1038/clpt.2011.34</pub-id>
</citation>
</ref>
<ref id="B93">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Takahashi</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Smith</surname>
<given-names>A. R.</given-names>
</name>
<name>
<surname>Jacobson</surname>
<given-names>P. A.</given-names>
</name>
<name>
<surname>Fisher</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Rubin</surname>
<given-names>N. T.</given-names>
</name>
<name>
<surname>Kirstein</surname>
<given-names>M. N.</given-names>
</name>
</person-group> (<year>2020</year>). <article-title>Impact of obesity on voriconazole pharmacokinetics among pediatric hematopoietic cell transplant recipients</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>64</volume>, <fpage>e00819</fpage>&#x2013;<lpage>20</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.00653-20</pub-id>
</citation>
</ref>
<ref id="B94">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Theuretzbacher</surname>
<given-names>U.</given-names>
</name>
<name>
<surname>Ihle</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Derendorf</surname>
<given-names>H.</given-names>
</name>
</person-group> (<year>2006</year>). <article-title>Pharmacokinetic/pharmacodynamic profile of voriconazole</article-title>. <source>Clin. Pharmacokinet.</source> <volume>45</volume>, <fpage>649</fpage>&#x2013;<lpage>663</lpage>. <pub-id pub-id-type="doi">10.2165/00003088-200645070-00002</pub-id>
</citation>
</ref>
<ref id="B95">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tian</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Qin</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>X.</given-names>
</name>
</person-group> (<year>2021</year>). <article-title>Impact of CYP2C19 phenotype and drug-drug interactions on voriconazole concentration in pediatric patients</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>65</volume>, <fpage>e0020721</fpage>. <pub-id pub-id-type="doi">10.1128/AAC.00207-21</pub-id>
</citation>
</ref>
<ref id="B96">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tissot</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Agrawal</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Pagano</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Petrikkos</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Groll</surname>
<given-names>A. H.</given-names>
</name>
<name>
<surname>Skiada</surname>
<given-names>A.</given-names>
</name>
<etal/>
</person-group> (<year>2017</year>). <article-title>ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients</article-title>. <source>Haematologica</source> <volume>102</volume>, <fpage>433</fpage>&#x2013;<lpage>444</lpage>. <pub-id pub-id-type="doi">10.3324/haematol.2016.152900</pub-id>
</citation>
</ref>
<ref id="B97">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Troke</surname>
<given-names>P. F.</given-names>
</name>
<name>
<surname>Hockey</surname>
<given-names>H. P.</given-names>
</name>
<name>
<surname>Hope</surname>
<given-names>W. W.</given-names>
</name>
</person-group> (<year>2011</year>). <article-title>Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>55</volume>, <fpage>4782</fpage>&#x2013;<lpage>4788</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.01083-10</pub-id>
</citation>
</ref>
<ref id="B98">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Valle-T-Figueras</surname>
<given-names>J. M.</given-names>
</name>
<name>
<surname>Miro</surname>
<given-names>B. R.</given-names>
</name>
<name>
<surname>Carabante</surname>
<given-names>M. I. B.</given-names>
</name>
<name>
<surname>Diaz-De-Heredia</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Bofarull</surname>
<given-names>J. V.</given-names>
</name>
<name>
<surname>Mendoza-Palomar</surname>
<given-names>N.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Voriconazole use in children: therapeutic drug monitoring and control of inflammation as key points for optimal treatment</article-title>. <source>J. Fungi</source> <volume>7</volume>, <fpage>17</fpage>. <pub-id pub-id-type="doi">10.3390/jof7060456</pub-id>
</citation>
</ref>
<ref id="B99">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Van Wanrooy</surname>
<given-names>M. J. P.</given-names>
</name>
<name>
<surname>Span</surname>
<given-names>L. F. R.</given-names>
</name>
<name>
<surname>Rodgers</surname>
<given-names>M. G. G.</given-names>
</name>
<name>
<surname>Van Den Heuvel</surname>
<given-names>E. R.</given-names>
</name>
<name>
<surname>Uges</surname>
<given-names>D. R. A.</given-names>
</name>
<name>
<surname>Van Der Werf</surname>
<given-names>T. S.</given-names>
</name>
<etal/>
</person-group> (<year>2014</year>). <article-title>Inflammation is associated with voriconazole trough concentrations</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>58</volume>, <fpage>7098</fpage>&#x2013;<lpage>7101</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.03820-14</pub-id>
</citation>
</ref>
<ref id="B100">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Vreugdenhil</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Van Der Velden</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Feuth</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Kox</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Pickkers</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Van De Veerdonk</surname>
<given-names>F. L.</given-names>
</name>
<etal/>
</person-group> (<year>2018</year>). <article-title>Moderate correlation between systemic IL-6 responses and CRP with trough concentrations of voriconazole</article-title>. <source>Br. J. Clin. Pharmacol.</source> <volume>84</volume>, <fpage>1980</fpage>&#x2013;<lpage>1988</lpage>. <pub-id pub-id-type="doi">10.1111/bcp.13627</pub-id>
</citation>
</ref>
<ref id="B101">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Walsh</surname>
<given-names>T. J.</given-names>
</name>
<name>
<surname>Anaissie</surname>
<given-names>E. J.</given-names>
</name>
<name>
<surname>Denning</surname>
<given-names>D. W.</given-names>
</name>
<name>
<surname>Herbrecht</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Kontoyiannis</surname>
<given-names>D. P.</given-names>
</name>
<name>
<surname>Marr</surname>
<given-names>K. A.</given-names>
</name>
<etal/>
</person-group> (<year>2008</year>). <article-title>Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America</article-title>. <source>Clin. Infect. Dis.</source> <volume>46</volume>, <fpage>327</fpage>&#x2013;<lpage>360</lpage>. <pub-id pub-id-type="doi">10.1086/525258</pub-id>
</citation>
</ref>
<ref id="B102">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wei</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Zhao</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Fu</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>X.</given-names>
</name>
</person-group> (<year>2019</year>). <article-title>Risk factors associated with insufficient and potentially toxic voriconazole plasma concentrations: an observational study</article-title>. <source>J. Chemother.</source> <volume>31</volume>, <fpage>401</fpage>&#x2013;<lpage>407</lpage>. <pub-id pub-id-type="doi">10.1080/1120009X.2019.1646974</pub-id>
</citation>
</ref>
<ref id="B103">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yan</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>Z. F.</given-names>
</name>
<name>
<surname>Tang</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>Y. W.</given-names>
</name>
<name>
<surname>Xu</surname>
<given-names>P.</given-names>
</name>
<etal/>
</person-group> (<year>2018</year>). <article-title>The impact of proton pump inhibitors on the pharmacokinetics of voriconazole <italic>in vitro</italic> and <italic>in vivo</italic>
</article-title>. <source>Biomed. Pharmacother.</source> <volume>108</volume>, <fpage>60</fpage>&#x2013;<lpage>64</lpage>. <pub-id pub-id-type="doi">10.1016/j.biopha.2018.08.121</pub-id>
</citation>
</ref>
<ref id="B104">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yang</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Du</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Xing</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Qiu</surname>
<given-names>B.</given-names>
</name>
</person-group> (<year>2023</year>). <article-title>Efficacy and influencing factor analysis of Voriconazole in the treatment of invasive fungal infections</article-title>. <source>Diagnostic Microbiol. Infect. Dis.</source> <volume>107</volume> (<issue>3</issue>), <fpage>116047</fpage>. <pub-id pub-id-type="doi">10.1016/j.diagmicrobio.2023.116047</pub-id>
</citation>
</ref>
<ref id="B105">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ye</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Yu</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Gu</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>L.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: a retrospective study</article-title>. <source>Front. Pharmacol.</source> <volume>13</volume>, <fpage>972585</fpage>. <pub-id pub-id-type="doi">10.3389/fphar.2022.972585</pub-id>
</citation>
</ref>
<ref id="B106">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yi</surname>
<given-names>W. M.</given-names>
</name>
<name>
<surname>Schoeppler</surname>
<given-names>K. E.</given-names>
</name>
<name>
<surname>Jaeger</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Mueller</surname>
<given-names>S. W.</given-names>
</name>
<name>
<surname>Maclaren</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Fish</surname>
<given-names>D. N.</given-names>
</name>
<etal/>
</person-group> (<year>2017</year>). <article-title>Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study</article-title>. <source>Ann. Clin. Microbiol. Antimicrob.</source> <volume>16</volume>, <fpage>60</fpage>. <pub-id pub-id-type="doi">10.1186/s12941-017-0235-8</pub-id>
</citation>
</ref>
<ref id="B107">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zeng</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Shi</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Zhu</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Luo</surname>
<given-names>J.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms</article-title>. <source>Eur. J. Clin. Pharmacol.</source> <volume>76</volume>, <fpage>515</fpage>&#x2013;<lpage>523</lpage>. <pub-id pub-id-type="doi">10.1007/s00228-020-02831-1</pub-id>
</citation>
</ref>
<ref id="B108">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhang</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Ji</surname>
<given-names>C.</given-names>
</name>
<etal/>
</person-group> (<year>2023</year>). <article-title>Factors influencing blood concentration of voriconazole and therapeutic drug monitoring in patients with child-pugh class C cirrhosis</article-title>. <source>J. Clin. Pharm. Ther.</source> <volume>2023</volume>, <fpage>1</fpage>&#x2013;<lpage>10</lpage>. <pub-id pub-id-type="doi">10.1155/2023/4240869</pub-id>
</citation>
</ref>
<ref id="B109">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Hou</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>M.</given-names>
</name>
<etal/>
</person-group> (<year>2021a</year>). <article-title>Predictors of voriconazole trough concentrations in patients with child-pugh class c cirrhosis: a prospective study</article-title>. <source>Antibiotics</source> <volume>10</volume> (<issue>9</issue>), <fpage>1542</fpage>. <pub-id pub-id-type="doi">10.3390/antibiotics10091130</pub-id>
</citation>
</ref>
<ref id="B110">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Hou</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>B.</given-names>
</name>
<etal/>
</person-group> (<year>2021b</year>). <article-title>A large sample retrospective study on the distinction of voriconazole concentration in asian patients from different clinical departments</article-title>. <source>Pharmaceuticals</source> <volume>14</volume> (<issue>12</issue>), <fpage>1239</fpage>. <pub-id pub-id-type="doi">10.3390/ph14121239</pub-id>
</citation>
</ref>
<ref id="B111">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhao</surname>
<given-names>Y. C.</given-names>
</name>
<name>
<surname>Zou</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Hou</surname>
<given-names>J. J.</given-names>
</name>
<name>
<surname>Xiao</surname>
<given-names>C. L.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>B. K.</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>J. K.</given-names>
</name>
<etal/>
</person-group> (<year>2021</year>). <article-title>Factors affecting voriconazole trough concentration and optimal maintenance voriconazole dose in Chinese children</article-title>. <source>Antibiotics-Basel</source> <volume>10</volume>, <fpage>1542</fpage>. <pub-id pub-id-type="doi">10.3390/antibiotics10121542</pub-id>
</citation>
</ref>
<ref id="B112">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhou</surname>
<given-names>P. Y.</given-names>
</name>
<name>
<surname>Lim</surname>
<given-names>T. P.</given-names>
</name>
<name>
<surname>Tang</surname>
<given-names>S. L. S.</given-names>
</name>
<name>
<surname>Liew</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Chua</surname>
<given-names>S. G. N.</given-names>
</name>
<name>
<surname>Lim</surname>
<given-names>L. L. C.</given-names>
</name>
<etal/>
</person-group> (<year>2020</year>). <article-title>The utility of voriconazole therapeutic drug monitoring in a multi-racial cohort in Southeast Asia</article-title>. <source>J. Glob. Antimicrob. Resist</source> <volume>21</volume>, <fpage>427</fpage>&#x2013;<lpage>433</lpage>. <pub-id pub-id-type="doi">10.1016/j.jgar.2019.12.004</pub-id>
</citation>
</ref>
</ref-list>
</back>
</article>