Pharmacokinetic-Pharmacodynamic Modelling of QT-Prolongation following Deliberate Self-Poisonings with Citalopram
Lena E Friberg(1), Geoffrey K Isbister(2), L Peter Hackett(3) and Stephen B Duffull(1)
(1)School of Pharmacy, University of Queensland; (2)Dept of Clinical Toxicology and Pharmacology, Newcastle Mater Hospital and Tropical Toxinology Unit, Charles Darwin University, Darwin; (3)Clinical Pharmacology and Toxicology, Western Australian Centre for Pathology and Medical Research, Australia
Objectives: Pharmacokinetic-pharmacodynamic (PKPD) models describing the time-course of QT-prolongation after overdoses would be valuable to predict the required time of observation and the probability of life-threatening toxicities. The antidepressant drug citalopram causes QT-prolongation more frequently compared to other SSRIs when taken in overdose [1], and has been implicated as a cause of Torsades de Pointes (TdP) [2,3]. The effect of activated charcoal administration in reducing the QT interval is not known. The aim of this study was to develop a PKPD model to describe the time-course of QT-prolongation after citalopram overdose and to evaluate the effect of charcoal on the risk of TdP.
Methods: A fully Bayesian method was used where prior information on the PK parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses while for PD parameters, biologically plausible prior distributions were applied. Plasma concentrations and ECG data from 53 patients after 63 citalopram overdose events (dose range: 20-1700 mg) were analysed in WinBUGS [4]. Activated charcoal was administered after 17 of the overdose events. The developed PKPD model was used for predicting the probability of having a QT interval greater than the 97.5th percentile of normal QT and heart rate combinations [5], here defined as an increased hazard for TdP, with and without charcoal.
Results: The PK data were described by a 1-compartment model with a baseline concentration in patients who were taking citalopram therapeutically, and an estimated uncertainty of the overdose amount. Activated charcoal was estimated to reduce the fraction absorbed by 22% and increase clearance by 72%. The absolute QT interval was related to the observed heart rate by a power function with an estimated individual heart rate correction factor. The heart rate corrected QT interval was linearly related to the predicted citalopram concentration in a hypothetical effect-compartment (teq=1.4 h). The heart rate corrected QT at baseline increased with female gender and with age. Charcoal significantly reduced the QT interval and was predicted to reduce the relative risk of TdP by approximately 60% for citalopram doses above 400 mg.
Conclusion: The developed PKPD-model may be useful for predicting the required time of observation after citalopram overdoses. Administration of activated charcoal significantly reduced the QT-interval and the relative risk for TdP.
References:
[1] Isbister GK et al. J Toxicol Clin Toxicol. 42: 277-85, 2004
[2] Tarabar et al. J Toxicol Clin Toxicol. 41: 676, 2003
[3] Meuleman et al. Arch Mal Coeur Vaiss 94: 1021-1024, 2001
[4] Spiegelhalter et al. http://www.mrc-bsu.cam.ac.uk/bugs
[5] Fossa et al. J Pharmacol Exp Ther 312: 1-11, 2005.