Yun Kim1, Anhye Kim2, Su-jin Rhee1, Eunwoo Kim1, Jae-Yong Chung3
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, 2Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea, 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea
Introduction: Escitalopram, a selective serotonin reuptake inhibitor as the S-enantiomer of racemic citalopram, is indicated for the treatment of major depressive disorder and generalized anxiety disorder (1). A thorough QT study identified that escitalopram had potential to prolong QT interval in dose-dependent manner, and showed the delay between its plasma concentration and QT interval prolongation (maximum QT prolongation delayed 3 h after the time to maximum plasma concentration) (2, 3). To evaluate the effect of escitalopram-induced QT prolongation considering the hysteresis in the exposure-response adequately, population pharmacokinetic (PK)/pharmacodynamic (PD) analysis can be a useful tool for the quantitative evaluation of the exposure-response relationship (4).
Objectives: This study aims to develop a population PK/PD model to characterize the relationship between escitalopram concentrations and the effect on QT prolongation based on the data from the thorough QT study.
Methods: Plasma concentrations of escitalopram and QT interval data were obtained from a previous thorough QT study in healthy volunteers after single dose administration of 20 mg escitalopram or placebo (2). A total of 40 healthy Korean volunteers participated in the study, and the data from completed number of participants of each placebo (all/male/female: 36/23/13) and escitalopram (all/male/female: 33/21/12) group was included in the population PK/PD analysis. Population PK/PD analysis was performed by using nonlinear mixed-effects modeling with NONMEM software (version 7.4.3.). A sequential PK/PD modeling approach was implemented as follows: First, the population PK model of escitalopram was constructed; second, a baseline QT model was developed based on the placebo QT interval data; third, the escitalopram concentration-drug effect model was finally developed with estimated individual PK and baseline QT parameters. Baseline QT model was developed in consideration of within-day variability based on 24-hour circadian rhythm (5). To explain the delay observed between escitalopram concentrations and QT prolongation, an effect compartment model was utilized.
Results: A two-compartment model with first-order absorption and lag time, first-order elimination and proportional residual error model adequately described the time-concentration profile of escitalopram. Only the body weight had a significant effect (?OFV: -11) on apparent volume of distribution in central compartment (Vc/F). A total of two harmonic cosine functions with periods of 24 and 12 hours adequately described the 24-hour circadian rhythm of baseline QT interval. Sex had a significant influence on the intercept of QT-RR relationship (QT0) (?OFV: -18.4), for which QT0 in female increased by 24 ms compared to that in male. A linear model adequately described the effect of escitalopram concentration on QT prolongation, compared to Emax and sigmoidal Emax models. According to the final PK/PD model, QT interval was described by the following equation: QT = (intercept of QT-RR relationship × sex effect × RRα) + (circadian rhythm effect) + (slope of concentration-QT × concentration in effect compartment). The average estimated maximal QT prolongation by drug effect was 5.4 ms (range: 1.9-7.6 ms) [slope of concentration-QT (0.232 ms/μg/L) multiplied by observed average Cmax (23.1 μg/L (range: 8.1-32.8 μg/L))]. The effect compartment equilibrium rate constant (Ke0) was estimated as 0.361 (1/h), which indicates the time delay between the concentration of escitalopram and QT prolongation (equilibrium half-life of delayed effect = 1.9 h). In addition, the drug effect of QTc change compared to that at baseline remained relatively constant from 1.3 to 3.5 ms over 24 h.
Conclusions: The present analysis was carried out as a follow-up study using the observed data from the previous thorough QT study. The developed PK/PD model well described the time course of the QT interval and evaluated the effect of escitalopram on QT prolongation and the time delay of escitalopram-induced QT prolongation.
References:
[1] Garnock-Jones KP, McCormack PL: Escitalopram: a review of its use in the management of major depressive disorder in adults. CNS Drugs 2010, 24:769-796.
[2] Kim A, Lim KS, Lee H, Chung H, Yoon SH, Yu KS, Cho JY, Jang IJ, Chung JY: A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers. Int Clin Psychopharmacol 2016, 31:210-217.
[3] Temple R, Laughren T, Stockbridge N: Removal from labeling of 60-mg citalopram dose. Pharmacoepidem Dr S 2012, 21:784-786.
[4] Piotrovsky V: Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation. AAPS J 2005, 7:E609-624.
[5] Chain AS, Krudys KM, Danhof M, Della Pasqua O: Assessing the probability of drug-induced QTc-interval prolongation during clinical drug development. Clin Pharmacol Ther 2011, 90:867-875.
Reference: PAGE () Abstr 9345 [www.page-meeting.org/?abstract=9345]
Poster: Drug/Disease Modelling - CNS