AUTHOR=Chen Bing , Shi Hao-Qiang , Feng Meihua Rose , Wang Xi-Han , Cao Xiao-Mei , Cai Wei-Min 

TITLE=Population Pharmacokinetics and Pharmacodynamics of Isoniazid and its Metabolite Acetylisoniazid in Chinese Population

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.932686

DOI=10.3389/fphar.2022.932686

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> We aimed to establish a population pharmacokinetic (PPK) model for isoniazid (INH) and its major metabolite Acetylisoniazid (AcINH) in healthy Chinese participants and tuberculosis patients and assess the role of the <italic>NAT</italic>2 genotype on the transformation of INH to AcINH. We also sought to estimate the INH exposure that would achieve a 90% effective concentration (EC<sub>90</sub>) efficiency for patients with various <italic>NAT2</italic> genotypes.</p><p><bold>Method:</bold> A total of 45 healthy participants and 157 tuberculosis patients were recruited. For healthy subjects, blood samples were collected 0–14 h after administration of 300 mg or 320 mg of the oral dose of INH; for tuberculosis patients who received at least seven days therapy with INH, blood samples were collected two and/or six hours after administration. The plasma concentration of INH and AcINH was determined by the reverse-phase HPLC method. <italic>NAT2</italic> genotypes were determined by allele-specific amplification. The integrated PPK model of INH and AcINH was established through nonlinear mixed-effect modeling (NONMEM). The effect of <italic>NAT2</italic> genotype and other covariates on INH and AcINH disposition was evaluated. Monte Carlo simulation was performed for estimating EC90 of INH in patients with various <italic>NAT</italic>2 genotypes.</p><p><bold>Results:</bold> The estimated absorption rate constant (K<sub>a</sub>), oral clearance (CL/F), and apparent volume of distribution (V<sub>2</sub>/F) for INH were 3.94 ± 0.44 h<sup>−1</sup>, 18.2 ± 2.45 L⋅h<sup>−1</sup>, and 56.8 ± 5.53 L, respectively. The constant of clearance (K<sub>30</sub>) and the volume of distribution (V<sub>3</sub>/F) of AcINH were 0.33 ± 0.11 h<sup>−1</sup> and 25.7 ± 1.30 L, respectively. The fraction of AcINH formation (F<sub>M</sub>) was 0.81 ± 0.076. <italic>NAT2</italic> genotypes had different effects on the CL/F and F<sub>M</sub>. In subjects with only one copy of NAT2 *5, *6, and *7 alleles, the CL/F values were approximately 46.3%, 54.9%, and 74.8% of *4/*4 subjects, respectively. The F<sub>M</sub> values were approximately 48.7%, 63.8%, and 86.9% of *4/*4 subjects, respectively. The probability of target attainment of INH EC<sub>90</sub> in patients with various NAT2 genotypes was different.</p><p><bold>Conclusion:</bold> The integrated parent-metabolite PPK model accurately characterized the disposition of INH and AcINH in the Chinese population sampled, which may be useful in the individualized therapy of INH.</p>