Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug-drug interactions and probability of target attainment. British Journal of Clinical Pharmacology
Courlet et al. aimed to develop (i) a population pharmacokinetics model for escitalopram in people living with human immunodeficiency virus (PLWH) and uninfected psychiatric individuals; (ii) to identify sources of variability that could influence drug exposure, and notably to evaluate drug-drug interactions (DDIs) involving antiretroviral agents; and (iii) to simulate expected exposures under standard dosage regimen and compare them with the established therapeutic reference range.
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.
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.
In conclusion, the pharmacokinetic model proposed in this study confirmed that escitalopram exhibits important between‐subject variability. Simulations revealed that the standard 10 mg once‐daily regimen may lead to trough concentrations below the established therapeutic target of 15 ng/mL, with a risk of suboptimal antidepressant efficacy. Dosage adjustment may benefit from both therapeutic drug monitoring (TDM) and monitoring of clinical efficacy and tolerability, taking into account other risks factors for QT prolongation, especially in elderly patients. These results emphasize the importance of TDM under specific conditions, such as therapeutic failure or suspected DDIs, for a proper individualization of dosing regimens. This study finally brings reassuring data concerning the risk of DDIs between escitalopram and others medications, including antiretrovirals.