Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug–drug interactions and probability of target attainment

Abstract

Aims The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug–drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen. Methods A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)‐infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under‐ or over‐exposed, considering established therapeutic targets (15–80 ng/mL). Results A 1‐compartment model with first‐order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV‐infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton‐pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model‐based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under‐exposed. Conclusion The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.

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

“…In this study, we created a PopPK model for oral administration of escitalopram in Chinese psychiatric patients, while considering demographic, genetic and physiological indicators. The model-predicted covariates of this analysis were in line with several published studies that describe the population pharmacokinetics of escitalopram (Jin et al, 2010;Akil et al, 2016;Courlet et al, 2019). We showed that CL/F of escitalopram varied nearly sevenfold, ranging from 6.26 to 38.93 L/h, which means that the pharmacokinetics of escitalopram in different populations show large interindividual variations.…”

“…We showed that CL/F of escitalopram varied nearly sevenfold, ranging from 6.26 to 38.93 L/h, which means that the pharmacokinetics of escitalopram in different populations show large interindividual variations. Some intensive sampling designs with escitalopram CL/F of 20-40 L/h, mostly in healthy Frontiers in Pharmacology frontiersin.org individuals (Søgaard et al, 2005;Nilausen et al, 2011;Chung et al, 2017), and published PopPK models have a CL/F > 20 or even 30 L/h (van Gorp et al, 2012;Courlet et al, 2019;Kim et al, 2021), while our study showed <20 L/h, which may have been caused by sparse data sampling. Similar to the previous PopPK studies, our analysis revealed that age and CYP2C19 phenotype contributed differentially to the variability in the pharmacokinetics of escitalopram.…”

“…The pharmacokinetics of escitalopram were best described by a one-compartment model with first-order absorption and elimination ( Courlet et al, 2019 ; Weisskopf et al, 2020 ). Owing to the proportional error model that could better describe the present model, we fixed the additive error to 0.…”

“…There have been several studies on the PopPK of escitalopram. The PK parameters have been compared in HIV-infected and uninfected psychiatric patients ( Courlet et al, 2019 ). A PopPK model of escitalopram in patients during the perinatal period has been established ( Weisskopf et al, 2020 ).…”

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.…”