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

Abstract

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range.Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations.Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients.Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.

Pharmacokinetics, Safety, and Tolerability of Brivaracetam in Healthy Elderly Participants

“…BRV hydroxylation into BRV-OH is mediated by CYP2C19. The clearance of some, but not all, CYP2C19 clinical substrates is reduced in the elderly because of decreased enzymatic activity with aging, for example, diazepam, [22][23][24][25][26] escitalopram, 34,35 and omeprazole. 36 Our data suggest that the formation of BRV-OH is not sensitive to age-related decrease in CYP2C19 activity.…”

Pediatric considerations for pharmacogenetic selective serotonin reuptake inhibitors clinical decision support

“…Similar to adult studies, some pediatric PGx studies have shown that escitalopram and citalopram exposure is significantly increased for patients who carry CYP2C19 variants, which can increase rates of adverse effects and discontinuation. An escitalopram pharmacokinetic modeling study showed CYP2C19 ( p < 0.001) and age ( p < 0.01) as significant covariants affecting exposure but not weight and concomitant medications 45 . A Danish cohort study of 17,297 patients, the majority of whom were ≤ 25 years old, found CYP2C19 PM children and adolescents ( n = 4039) who were using (es)citalopram were 1.6 times more likely to switch to a different drug compared with CYP2C19 NM (incidence rate ratio (IRR) = 1.64 [95% confidence interval (CI): 1.10–2.43]) 46 .…”

“…An escitalopram pharmacokinetic modeling study showed CYP2C19 (p < 0.001) and age (p < 0.01) as significant covariants affecting exposure but not weight and concomitant medications. 45 A Danish cohort study of 17,297 patients, the majority of whom were ≤ 25 years old, found CYP2C19 PM children and adolescents (n = 4039) who were using (es)citalopram were 1.6 times more likely to switch to a different drug compared with CYP2C19 NM (incidence rate ratio (IRR) = 1.64 [95% confidence interval (CI): 1.10-2.43]). 46 In addition, attempted suicide or self-harm was 2.7 times more likely in CYP2C19 PM than those who were CYP2C19 NM (IRR = 2.67 [95% CI; 1.57-4.52]).…”

Escitalopram Personalized Dosing: A Population Pharmacokinetics Repository Method

“…To date, several PPK studies on SCIT have been conducted to identify the covariates that may significantly affect the PK characteristics. [16][17][18][19][20][21][22][23] For instance, the influence of CYP2C19 polymorphism on SCIT exposure was found to be substantial. Consequently, diverse dosage regimens were simulated to enable personalized dosing recommendations for distinct populations.…”

“…Consequently, diverse dosage regimens were simulated to enable personalized dosing recommendations for distinct populations. 17,[20][21][22][23] Notably, Liu's report highlighted that older patients with poor metabolizer status may be at risk of adverse effects and potential overdosing when administered with 15 or 20 mg SCIT. 21 Therefore, the authors strongly advised exercising heightened vigilance in monitoring this specific population to mitigate potential risks.…”