Pharmacokinetic–pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

doi:10.1111/j.1365-2125.2005.02546.x

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Wiley InterScience

British Journal of Clinical Pharmacology

Volume 61 Issue 2, Pages 177 - 190

Published Online: 1 Dec 2005

The Journal of The British Pharmacological Society

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Pharmacokinetic–pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

Lena E. Friberg ² , Geoffrey K. Isbister ¹ & Stephen B. Duffull ²

² School of Pharmacy, University of Queensland, Brisbane, Australia , and ¹ Department of Clinical Toxicology and Pharmacology, Newcastle Mater Hospital, Newcastle and Tropical Toxinology Unit, Menzies School of Health Research, Charles Darwin University, Darwin, Australia

Correspondence to Lena E. Friberg, Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Tel: + 46 18 471 4685
Fax: + 46 18 471 4003
E-mail: lena.friberg@farmbio.uu.se

L.E.F. current address: Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Sweden.

KEYWORDS

activated charcoal • citalopram • modelling • pharmacodynamics • QT interval • toxicology

ABSTRACT

Aims

To develop a pharmacokinetic–pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations.

Methods

Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic–pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP).

Results

The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [α = 0.36, between-subject coefficient of variation (CV) = 29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg⁻¹, between-subject CV = 70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg.

Conclusion

Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.

Received 19 September 2005 Accepted 26 September 2005

DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1365-2125.2005.02546.x About DOI