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

Abstract

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.

Inhibitory effect of napabucasin on arbidol metabolism and its mechanism research

“…Arbidol is mainly metabolized by the CYP3A4 isoenzyme in humans, so theoretically inducers or inhibitors of CYP3A4 will affect the metabolism of arbidol. LPV/r as protease inhibitors had a significant interaction with arbidol, which increased the C max and AUC (0-∞) of both drugs ( Huang et al, 2021 ). In this experiment, napabucasin is found to be a bioactivator of quinone oxidoreductase 1 that generates reactive oxygen species ( Chang et al, 2019 ; Froeling et al, 2019 ).…”

“…For example, the combination of lopinavir/ritonavir (LPV/r) and arbidol will be a risk factor for liver injury in patients with non-critical COVID-19 ( Cai et al, 2020 ). Studies reported that when LPV/r was combined with arbidol, the C max of arbidol was increased and the AUC (0-∞) of arbidol was significantly increased from 705.6 to 1250.3 ng/mL*h ( Huang et al, 2021 ). In addition, pharmacokinetic and metabolic differences caused by administration of arbidol were found in male and female rats.…”

Escitalopram Personalized Dosing: A Population Pharmacokinetics Repository Method

“…5,[8][9][10] However, only 50%-60% of patients respond to SCIT, 11 this may be partially ascribed to inter-individual (IIV) differences in metabolic capacity, influenced by genetic variability in drug-metabolizing enzymes, specifically the hepatic cytochrome P450 (CYP) system. [12][13][14][15] Consequently, using a one-size-fits-all approach for all patients could lead to treatment failure and unexpected adverse drug reactions.…”

Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age

“…Escitalopram is primarily metabolized in the liver by cytochrome P (CYP)450, particularly CYP2C19, which is a highly polymorphic enzyme that causes interindividual pharmacokinetic differences ( Rao, 2007 ; Pastoor and Gobburu, 2014 ), and is excreted mainly through the kidneys. The effect of age ( Dolder et al, 2010 ; Yang and Scott, 2010 ), gender ( Montejo et al, 2015 ), smoking ( Oliveira et al, 2017 ; Scherf-Clavel et al, 2019 ), CYP2C19 phenotype ( Huang et al, 2021 ), hepatic impairment ( Areberg et al, 2006 ), and renal impairment ( Dolder et al, 2010 ) on the pharmacokinetics of escitalopram have been investigated. The findings of these studies were instrumental in developing specific dosing recommendations for escitalopram for specific populations ( Hicks et al, 2015 ; Brouwer et al, 2021 ).…”