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

Abstract

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 2.6 h 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.

Figure 1

Observed dose-normalized concentrations (to the average therapeutic dose of 20 mg) vs. reported time of administration. Samples from the same dose event are connected. The symbols denote if the patient was not administered SDAC (•) or was administered SDAC (×)

Figure 2

Comparison of the individual predicted dose normalized area under the curve (AUC_k/dose) estimations for patients not receiving SDAC (○) vs. patients receiving SDAC (•); median indicated by horizontal line

Figure 3

Simulated plasma concentrations (—) and QT intervals (- - -) vs. time in a patient with typical PK and PD parameters for an escitalopram overdose without SDAC (A). Simulated QT intervals vs. time without (—) and with (- - -) SDAC (B). The dose was 300 mg and the RR interval 770 ms (HR = 78 bpm) for both panels

Figure 4

Plots of the fraction of patients with an abnormal QT (QT >447 ms, RR = 762 ms) vs. time for doses ranging from 50 mg to 400 mg. A) shows the fraction of patients without SDAC and B) the fraction of patients with SDAC. Five thousand patients were simulated and assumed to be 30-year-old women taking escitalopram therapeutically

Figure 5

Plot of the relative decrease in cumulative hazard for having an abnormal QT interval (≥447 ms, RR = 762 ms) when SDAC is administered for doses ranging from 50 mg to 400 mg

Figure 6

Predicted individual clearance values for citalopram (grey lines), with and without charcoal, compared with values for escitalopram (dark points), with and without charcoal. Clearance values for citalopram were predicted using the previously published PKPD model of citalopram [2]. Escitalopram (♦); Citalopram (◊)