Population pharmacokinetic/pharmacodynamic modeling of delayed effect of escitalopram-induced QT prolongation

Abstract

BackgroundA thorough QT study identified that escitalopram-induced QT prolongation was delayed. This study thus aimed to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to characterize the relationship between escitalopram concentrations and the delayed effect on QT prolongation. MethodsThe data of completed subjects who had placebo (n=36) and a single dose of 20 mg escitalopram (n=33) from a previous thorough QT study were used. Population PK/PD analysis was performed by nonlinear mixed-effects modeling. A escitalopram concentration-drug effect model was developed with estimated individual PK and baseline QT parameters. To explain the relationship between escitalopram concentrations and QT prolongation delay, an effect compartment model was utilized. ResultsA two-compartment model with first-order absorption and lag time and first-order elimination adequately described the PK of escitalopram. The circadian rhythm of baseline QT interval was best explained by two harmonic cosine functions. A linear model properly characterized escitalopram-induced QT prolongation. The average estimated maximal QT prolongation was 5.4 ms (range: 1.9-7.6 ms). The equilibrium half-life of delayed QT prolongation was 1.9 h. The drug effect of QTc change compared with that at baseline remained relatively constant from 1.3 to 3.5 ms over 24 h, and the maximum QTc change occurred with a 3-h delay after the time to the maximum plasma concentration. LimitationsWe did not include genetic polymorphisms, such as CYP2C19, as potential covariates owing to limited information. ConclusionsThese results may provide useful information on when to monitor electrocardiogram in patients who require intensive care after drug administration.