CYP2C19 Genotyping May Provide a Better Treatment Strategy when Administering Escitalopram in Chinese Population

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, open-label, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results provide the evidence of individual treatment of escitalopram in Chinese, which will be beneficial for the safer and more effective application of escitalopram in the Chinese population. Clinical Trial Registration: identifier ChiCTR1900027226.

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, openlabel, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results

INTRODUCTION
Depression disorder is a common mental disease that might lead to considerable difficulty with daily functioning (Cipriani et al., 2009). More seriously, the patients with severe depression showed a higher suicide rate than other mental diseases; the number of suicides from depression is estimated to reach 1 million each year worldwide (WHO Guidelines Approved by the Guidelines Review Committee, 2016). The World Health Organization (WHO) has warned depression disorder as a leading cause of disability around the world and significantly contributes to the global burden of disease (WHO Guidelines Approved by the Guidelines Review Committee, 2016). The situation of depression disorder in China is not optimistic either: At present, the incidence rate in China is about 3-5 percent, i.e., more than 36 million people suffer from depression disorder in China (Yu et al., 2021). Therefore, it is essential to treat and manage depression disorder.
Antidepressant is one of the key strategies to treat depression disorder (Sinyor, 2019). Escitalopram is an essential selective serotonin reuptake inhibitor (SSRI) antidepressant, which binds to the serotonin transporter protein (SERT) and inhibits the reuptake of serotonin by the presynaptic neuron (Stahl, 1998;Landy and Estevez, 2021). It is the (S)-enantiomer of citalopram, another SSRI antidepressant. Because the (S)-enantiomer of citalopram demonstrated significantly more potency than the (R)-enantiomer of citalopram relative to the serotonin reuptake and inhibition, escitalopram shows higher potency than citalopram (Rao, 2007). Therefore, it is widely used in the treatment of major depressive disorder and generalized anxiety disorder (Stahl, 1998;Landy and Estevez, 2021 (Ji et al., 2014). CYP2C19 exhibits 35 different types of gene alleles of gene polymorphism (PharmaVar, 2021). Among these gene alleles, the *1 allele is wild type with normal function; the *17 allele is the allele with increased enzyme activity; and the *2 and *3 alleles are the major variants (Ding et al., 2015). The effect of CYP2C19 on the pharmacokinetics (PK) and pharmacodynamics (PD) on the Caucasian population has been studied: The subjects with the * 17 allele showed faster metabolisms, and the *2 and *3 alleles showed poorer metabolisms of escitalopram (Chang et al., 2014;Jukić et al., 2018). The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population (Hicks et al., 2015). However, CYP2C19 shows different mutation rates in different races over the world: the frequency of the *2 and *3 alleles have been shown as 29-35% and 5-9% in Asians, whereas the frequency in Caucasians is 12-15% and <1%. The frequency of the *17 allele is reported to be higher in Caucasians (16-21%), but relatively lower (3-6%) in Asians (Dorji et al., 2019;Zhou et al., 2019). In addition, the environments may also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. Escitalopram was approved for usage in China for 15 years, and it is the first-line antidepressant medication in China (Li et al., 2020). Therefore, it is necessary to evaluate the effect of CYP2C19 genotypes on the PK parameters on Chinese population to provide a basis for the individualized medication guidance of escitalopram in China. For safer and more effective usage of escitalopram, the effect of food and gender on escitalopram also needs to be evaluated on Chinese populations (Chang et al., 2014;Jukić et al., 2018).
In this study, we evaluated the PK profiles of escitalopram under fasting and fed conditions in male and female subjects. Then, the effect of CYP2C19 genotypes on the PK parameters of escitalopram was also evaluated. The steady-state blood concentration (C ss ) of escitalopram was predicted from the PK parameters of different genotypes to provide the evidence to speculate as it is necessary to adjust the dose of escitalopram according to the genotypes in Chinese population.

Subjects
Subjects were screened for eligibility approximately 1 week before dosing. Screening included medical history, vital signs, physical examination, clinical laboratory tests, and 12-lead electrocardiogram (ECG) recording. All the subjects were eligible based on the following criteria: age ≥18 years old, both male and female; male subjects' weight ≥50 kg, female subjects' weight ≥45 kg; body mass index between 19 and 26 kg/m 2 . Exclusion criteria included the following: subjects with any significant, acute, chronic, or infectious disease of the respiratory system, circulatory system, cardiovascular system, digestive system, nervous system, etc.; subjects that used concomitant treatments before or during the study period (i.e., being within 4 weeks of exposure to surgery, within Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 730461 30 days of using any drug that inhibits or induces hepatic metabolizing enzymes, and within 14 days of using any medicines), alcohol abuse, etc.; female subjects who were pregnant, nursing, or rejected using more than one type of adequate contraception. All the eligible subjects were apprised of the risks of the trial and read, understood, and signed the written informed consent forms prior to participation. A subject had to be removed from the study if the subject withdrew the consent, if the investigator considered it appropriate for patient's safety reasons, or if the subject missed the follow-up.

Study Design
The data obtained from the results of subjects treated with a reference formulation in two single-center, randomized, openlabel, two-period, two-treatment crossover bioavailability studies used the same reference formulation of escitalopram conducted at Changsha Central Hospital, China. In total, 96 healthy adult subjects were enrolled in the study, 48 subjects in each clinical trial. These clinical trials included fasting and fed tests, and both the groups included males and females. The protocols were approved by the Independent Ethics Committee of Changsha Central Hospital. The clinical trial was registered in Chinese Clinical Trial Registry (Registration number: ChiCTR1900027226).
These studies consisted of two periods with a 2 weeks washout interval. All the subjects fulfilling the criteria were randomly stratified by gender to ensure the presence of male and female subjects in each group. Then, the subjects were provided a random number by using a table of random numbers generated by using SAS 9.4 software (SAS Inc., Cary, USA).
Subjects received a single dose of 10 mg escitalopram tablet according to the random numbers within 30 min after a 10 h fasting period or within 30 min after beginning the consumption of a recommended high fat breakfast (150 calories of protein, 250 calories of carbohydrates, 500-600 calories of fat; total calories approximately 800-1,000). Tablets were administered with 240 ml of water to each subject in each period. Drinking was prohibited for 1 h before and after medication. Apart from this, the amount and time of drinking were not strictly controlled.
Subjects had unified, standard meals 4 and 10 h after drug administration.
The composition of meal was determined based on the FDA guidelines and consisted of two fried eggs, two fried fritters, and 250 ml of whole milk. The detailed composition and calories of the HF meal used in this study are shown in Supplementary  Table S1.
Descriptive statistics of PK parameters were calculated using established noncompartmental methods, utilizing the WinNonLin version 6.3 software (Pharsight Corporation, USA). The PK parameters determined for each participant included apparent terminal half-life (t 1/2 ), maximum plasma concentration (C max ), time to C max (t max ), area under the plasma concentration-time curve from the time of administration up to the last time point with a measurable concentration post-dose (AUC 0-t ), AUC extrapolated to infinity (AUC 0-∞ ).

Analytical Methods
All the samples were detected by liquid chromatography (UPLC I-Class, Waters company, USA) -Tandem Mass Spectrometry (Xevo TQ-S, Waters company, USA) (LC-MS/MS) method, validated at Duxact Biotech Co., Ltd. (Changsha, China). A brief description of the method is as follows. The plasma samples were pretreated by protein precipitation method. The internal standard is escitalopram-D4. Using Waters ACQUITYUPLC-HSS T3 1.8 μm (2.1 mm × 50 mm) chromatographic column, 0.2% formic acid aqueous solution (phase A)-acetonitrile (phase B) as the mobile phase, isocratic elution, flow rate 0.4 ml·min −1 . An electrospray ion source (ESI) and a positive ion multireaction monitoring mode for detection were used. The ion pairs of escitalopram and internal standard escitalopram-D4 are m/z 325.24→m/z109.16 and m/z 329.22→m/z 113.14, respectively. The linear range is 0.100-25.000 ng/ml. The retention time of analyte and internal standard is 0.570 ± 0.1 min. The single injection time is 1.2 min.
It was selective, accurate, and precise. The accuracy ranged from 90.8 to 107.2% of the true value. The intra-batch and inter-Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 730461 batch ranged from 2.0 to 3.2% and from 2.8 to 5.3% of the relative standard deviation (RSD), respectively. The lower limit of detection was 0.1 ng/ml. The calibration curve was linear over the concentration range of 0.2-100 ng/ml, with r 2 > 0.999. Escitalopram plasma sample could be stored at -70°C for at least 93 days and was stable for more than 50 h when left at room temperature. Escitalopram in plasma was stable after three freeze-thaw cycles. The final processed sample could be left in autosampler at 15°C for at least 24 h. The stock solutions of escitalopram could be kept at -20°C for at least 47 days. According to this analytical method validation data according to the currently accepted US FDA bioanalytical method validation guidance, this modified method for the determination of escitalopram in plasma was considered reliable and suitable for pharmacokinetic study of escitalopram.

Prediction of Steady-State Blood Drug Concentration
Escitalopram is rapidly and nearly completely absorbed in human (Rao, 2007); In addition, possible confounding factors in this clinic trial, including gender and food, had been excluded. Last, the parameters in the formula are available based on our clinical trials. Therefore, the prediction of average C ss (C av, ss ) and minimum C ss (C ss, min ) for different types of metabolizers could be calculated from the PK parameters using Formulas 2-1 and 2-2: The prediction of dose was calculated using Formula 2-3: F, bioavailability; DM, maintenance dose; CL, apparent plasma clearance; V, apparent volume of distribution, k, elimination rate constant; τ, dosing interval.
The WinNonLin version 6.3 software (Pharsight Corporation, USA) was utilized to establish the predicted schematic diagram of multiple doses.

Statistical Methods
The concentrations of escitalopram were measured as the mean concentration of each time point and standard deviation (SD), except for t max , which was expressed as median (range). The major PK parameters such as t max , t 1/2 , AUC, and C max under fasting or fed conditions, male or female subjects, and genotypes were statistically analyzed using SAS software (SAS Institute Inc., USA).
Analysis of Variance (ANOVA) was conducted after the natural log-transformation of major PK parameters to evaluate the effects of food, gender, and genotype on the PK of escitalopram.

Equivalence Test of Two Clinical Trials
The equivalence test showed no statistical difference in the main PK parameters between trails 1 and 2 (Supplementary Table S2). Although AUC 0-∞ 90% CI fell in 79-106, it still showed no statistical difference between trail 1 and trail 2. Therefore, the data obtained from these two trails could be combined for the subsequent analysis.

Demographic Characteristics
In total, 96 healthy subjects were enrolled in this study. All the subjects met the eligibility criteria for the protocol. Six subjects withdraw from the clinical trial; therefore, 90 healthy subjects (67 males and 23 females) were included in the statistical analysis. Baseline demographics across both the groups are shown in Table 1.

Effect of Food
The fasting and fed tests were used to evaluate if food affects the PK parameters of escitalopram. All the available PK parameters recorded for each subject were included in the PK assessments, summary statistics, and statistical analyses, as predefined in the study protocol. The mean plasma concentration-time curves for the fasting and fed tests of escitalopram are shown in Supplementary Figure S1. A summary of the PK parameters of fasting and fed tests of escitalopram is shown in Table 1. The equivalence test showed the ratio 90% CI fell in 80-125%, i.e., the fasting test and fed test were equivalent, indicating that there was no statistical difference between these two treatments (Supplementary Table S2). These results show that food might not affect the PK parameters of escitalopram on Chinese population.

Effect of Gender
To confirm the effect of gender, the PK parameters of female and male subjects were also analyzed. The summary of PK parameters of escitalopram for female and male subjects is Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 730461 shown in Table 1. The mean plasma concentration-time curves of escitalopram for different genders are shown in Figure 1. The equivalence test showed that the ratio 90% CI fell in 80-125%, i.e., the main PK parameters of male subjects and female subjects were equivalenced, indicating that there was no statistical difference between these two treatments (Supplementary Table S2). These results show that gender might not influence the PK parameters of escitalopram in Chinese population.

Effect of Genotype
According to our results, food and gender might not affect the PK parameters of escitalopram; therefore, the PK parameters were analyzed by genotype without considering about food and gender. Out of 90 candidates, the DNA quality of 88 candidates satisfied the sequencing requirements. Among these candidates, 13 subjects were CYP2C19 PMs with a CYP2C19 genotype of *2/ *2 allele (n 11), *3/*3 allele (n 1), and *2/*3 allele (n 1), 47 subjects were CYP2C19 IMs with a CYP2C19 genotype of *1/*2 allele (n 37) and *1/*3 allele (n 10), 37 subjects were CYP2C19 EMs with a CYP2C19 of *1/*1 allele (n 39); one subject was CYP2C19 UM with a CYP2C19 of *1/*17 allele (n 1). The UM was not included in the analysis due to the lack of candidates. The ANOVA was used to compare the PK parameters in different types of metabolizers.
The results indicate that most of the PK parameters showed statistically difference between different types of metabolizers. AUC 0-t , AUC 0-∞ , and t 1/2 were statistically different among those three types of metabolizers: Compared with the EM, the exposure to escitalopram increased by 106% (95%CI, 61-162); t 1/2 of Age and BMI expressed as range (mean ± standard), t max expressed as median for range. Other values are presented as mean ± standard deviation. BMI, body mass index; t 1/2 , participant included apparent terminal half-life; C max , maximum plasma concentration; t max , time to C max ; AUC 0-t , area under the plasma concentration-time curve from the time of administration up to the last time point with a measurable concentration post-dose; AUC 0-∞ , AUC extrapolated to infinity. Compared with the IM, the exposure to escitalopram increased by 41% (95%CI, 13-77); t 1/2 of escitalopram increased by 32% (95 %CI, 12-56) in the PM. However, C max was not statistically different among the IM, EM, and PM. The PK parameters of IM are closed to the total subjects. The summary of PK parameters of escitalopram for the IM, EM, PM, and all the subjects is shown in Table 2. The PK parameters of IM are similar to the results of all subjects without distinguishing the genotypes. The analysis of PK parameters of the metabolizers is shown in Table 3. The mean plasma concentration-time curves of escitalopram for the three types of metabolizers and total subjects are shown in Figure 2. Values are presented as mean ± standard deviation. t max expressed as median for range. t 1/2 , participant included apparent terminal half-life; C max , maximum plasma concentration; t max , time to C max ; AUC 0-t , area under the plasma concentration-time curve from the time of administration up to the last time point with a measurable concentration post-dose; AUC 0-∞ , AUC extrapolated to infinity. The ANOVA was used in analysis. CI Confidence Interval. C max , maximum plasma concentration; AUC 0-t , area under the plasma concentration-time curve from the time of administration up to the last time point with a measurable concentration post-dose; AUC 0-∞ , AUC extrapolated to infinity. The main PK parameters were obtained from these single dose clinical trials. However, the treatment of depression disorder is a long-term process, and escitalopram often has multiple doses in the clinical treatment (Gartlehner et al., 2016). According to previous reports and clinical guideline, 10 mg/d is the common clinical treatment dose, which is the same as the single dose in this study (Hicks et al., 2015;Gartlehner et al., 2016). The bioavailability of escitalopram was reported as 80% (Rao, 2007). Therefore, it is available to predict the C av, ss and C ss, min according to the PK parameters using Formulation 2-1 and 2-2. The summary of C av, ss and C ss, min of escitalopram for the IM, EM, and PM, and all the subjects are shown in Table 4; the prediction of IM is similar to the results of all subjects without distinguishing genotypes. The ANOVA was used to compare the results among different type of metabolizers.
The results indicate that C av, ss and C ss, min were statistically different among different types of metabolizer in Chinese population. Compared to the EM, the C av, ss of escitalopram increased by 106% (95 %CI, 61-162); the C ss, min of escitalopram increased by 139% (95% CI, 80-217) in the PM; compared with the IM, the C av, ss of escitalopram increased by 41% (95 %CI, 13-77); the C ss, min of escitalopram increased by 51% (95 %CI, 13-77) in the PM. The results of IM are close to the total subjects. The analysis of C av, ss and C ss, min of different types of metabolizers is shown in Table 5. The predicted schematic diagram of multiple doses to reach the calculated predicted C ss All values are presented as mean ± standard deviation. C av, ss , average steady-state blood concentration; C ss, min , minimum steady-state blood concentration. The ANOVA was used in analysis. CI Confidence Interval. C av, ss , average steady-state blood concentration; C ss, min , minimum steady-state blood concentration. on different metabolizers and total subjects are shown in Figure 3. A preliminary prediction of dose was obtained using Formulation 2-3: The results show that compared with all the subjects, it is necessary to decrease 22% of dose in the PM and increase 59% of dose in the EM.

DISCUSSION
As an SSRI, escitalopram is widely used in the treatment of depression disorder and anxiety disorder (Yu et al., 2021). Its efficacy and toxicity show variation among different genotypes in previous studies (Chang et al., 2014;Jukić et al., 2018). Although escitalopram has been approved in China for about 15 years, there is a lack of data on the PK parameters of different genotypes in the Chinese population. Therefore, the effect of different genotypes was evaluated in 96 healthy Chinese subjects, and other factors such as food and gender that might alter the PK parameters were also considered in this study. The C ss was predicted by PK parameters using formulas to simulate clinical medication. The results show that food and gender might not affect the PK parameters of escitalopram, and the genotypes might be one of the major factors that affect the PK parameters of escitalopram. The prediction indicates that the PM has increased C ss than the EM and IM, which might provide evidence for the adoption of escitalopram dosage in Chinese population. During the study, no drug combination occurred in the subjects; therefore, there was no potential effect of drug-drug interactions on PK parameters. The PK parameters showed no statistical difference between the fed and fasting groups, i.e., food might not alter the PK parameters in Chinese population. The results are similar with the results of previous studies in other races (Søgaard et al., 2005;Li et al., 2020;Landy and Estevez, 2021), indicating that escitalopram can be administered with or without meals in Chinese population. Then, the PK parameters showed no statistical difference between male and female, i.e., gender does not affect the PK parameters in Chinese population. The same results were obtained in the studies on other races like Egyptian population and Caucasian population (ElKady et al., 2018;Landy and Estevez, 2021). The CYP2C19 genotypes might play a key role in the PK parameters of escitalopram: The PM had the highest AUC 0-t and AUC 0-∞ , and the longest t 1/2 than the EM and IM. Different C max levels were found among the three types of phenotypes, but they were not significant, i.e., the degree of CYP2C19 genotype effects on C max might not be as deep as other PK parameters. The results of AUC show that the PM might have higher exposure than EM in Chinese population, which might affect the efficacy and safety of escitalopram treatment. The same results were reported in other populations, although the specific PK parameters were not exactly the same: The effects of individual variation on the efficacy and toxicity of different CYP2C19 genotypes were reported in patients of Caucasian population and Brazilian population (Chang et al., 2014;Jukić et al., 2018;Bernini de Brito and Ghedini, 2020;Landy and Estevez, 2021;Milosavljevic et al., 2021). Because of a higher mutation rate of the PM CYP2C19 genotype in Chinese population, the association between metabolizers and individual variations should be considered in the treatment of escitalopram in Chinese population (Dorji et al., 2019;Zhou et al., 2019). However, escitalopram often has multiple doses in the clinical treatment, and C ss is a key factor reflecting the status of clinical medication (Landy and Estevez, 2021). The common clinical dosing regimen of escitalopram and dosing interval are used to predict the C av, ss and C ss, min of different types of metabolizers. Although C max showed no statistical difference in single dose results, the prediction showed that compared with the EM, the C av, ss and C ss, min of escitalopram increased by 106 and 139% in the PM, respectively. The increased C ss, min indicates the rising risk of side effects in the treatment of escitalopram. The therapeutic window of escitalopram is still not clear enough. Most of the studies focus on the pharmacokinetics of escitalopram did not provide the C ss of escitalopram. From the existing reports: the rational C ss of escitalopram (10 mg/d) in humans are from 8 to 52 ng/ml, which were consistent with the results in this study (Rao, 2007;Chang et al., 2014;Jukić et al., 2018). The results indicate that the genetic testing of CYP2C19 genotype is necessary before the treatment of escitalopram in Chinese population. The same recommendations were provided by the studies in Caucasian population according to the Clinical Pharmacogenetics Implementation Consortium (Hicks et al., 2015). The preliminary prediction showed that compared with all the subjects, it is necessary to decrease 22% of dose in the PM and increase 59% of dose in the EM. However, the initial therapy dose and the reducing dosage of escitalopram in Chinese population need to be investigated in the follow-up research.
Some limitations of this study are as follows: First, the unavailability of UM data was attributed to the limited simple size and the low gene frequency in Chinese population (Dorji et al., 2019). Secondly, the effect of age was not considered in our study, although it was reported to be associated with the PK parameters of escitalopram (Waade et al., 2014;Landy and Estevez, 2021). Thirdly, the clinical trials were only conducted in healthy populations, without considering the changes in PK under disease states and the efficacy of escitalopram. Lastly, the C ss was preliminarily predicted using the PK formula which may not fully represent the universal data. In future studies, it is necessary to conduct clinical trials considering a sufficient number of subjects for each genotype and the influence of age and disease state in Chinese population. The clinical trials enrolling patients to investigate the efficacy and toxicity of escitalopram of different metabolizers in Chinese population should also be considered in the future. In addition, the clinical trials with multiple doses of escitalopram should also be considered to assess the certain C ss data in Chinese population in follow-up research.
In summary, the PK parameters in Chinese population obtained in our study might help to determine the clinical dosing regimen and design follow-up studies. The intraindividual variation of exposure of escitalopram was 30.92%, providing a basis to be used in sample size estimations of Chinese population in future clinical trials. The PK parameters showed that the exposure of escitalopram was higher in the PMs in Chinese population. These results indicate that a decreased dose of escitalopram in the PM on Chinese population should be considered due to the higher frequency of PM in Chinese population than that in Caucasian populations (Myrand et al., 2008). The prediction that the C ss in different metabolizers may be different suggests that genotype might be a prerequisite for determining the dosage of escitalopram in Frontiers in Pharmacology | www.frontiersin.org August 2021 | Volume 12 | Article 730461 Chinese population. Further research should be conducted to establish a guideline for the dosing of CYP2C19 genotypes in Chinese population as in Caucasian populations (Hicks et al., 2015). Our results suggested that to decrease the toxicity and increase the efficacy of escitalopram in Chinese population, genetic testing before medication, adjustment of dose, and therapeutic drug monitoring should be considered in the clinical treatment of escitalopram. The results indicated CYP2C19 genotyping may provide a better treatment strategy when administering escitalopram in Chinese population, which will be beneficial for a safer and more effective application of escitalopram in the Chinese population.

CONCLUSION
Based on the results of this study, in Chinese population, food and gender might not affect the PK parameters of escitalopram, while CYP2C19 might affect it: The PM might have a higher exposure and t 1/2 than the EM and IM. The prediction of C ss indicates that PM might have a higher plasma concentration of escitalopram, which reminds us that genetic testing should be conducted before the medication, and the adjustment of escitalopram in the PM should be considered in the clinical treatments in Chinese population.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Independent Ethics Committee of Changsha Central Hospital. The patients/participants provided their written informed consent to participate in this study.