Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

Aims: To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC). Methods: The data set included 78 escitalopram overdose events (median dose, 140mg [10-560mg]). SDAC was administered 1.0 to 2.6h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes. Results: A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC _i/dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α= 0.35). The heart rate corrected QT interval (QT _c) was linearly dependent on predicted escitalopram concentration [slope = 87ms/(mgl ^-1)], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200mg. Conclusions: There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.