Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

Friberg, L. E., Isbister, G. K. and Duffull, S. B. (2006) Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses. British Journal of Clinical Pharmacology, 61 2: 177-190. doi:10.1111/j.1365-2125.2005.02546.x


Author Friberg, L. E.
Isbister, G. K.
Duffull, S. B.
Title Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses
Journal name British Journal of Clinical Pharmacology   Check publisher's open access policy
ISSN 0306-5251
1365-2125
Publication date 2006-01-01
Sub-type Article (original research)
DOI 10.1111/j.1365-2125.2005.02546.x
Volume 61
Issue 2
Start page 177
End page 190
Total pages 14
Place of publication London
Publisher Blackwell Science
Language eng
Subject C1
320504 Toxicology (incl. Clinical Toxicology)
730399 Health and support services not elsewhere classified
1115 Pharmacology and Pharmaceutical Sciences
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 [alpha = 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.
Keyword Pharmacology & Pharmacy
Activated Charcoal
Citalopram
Modelling
Pharmacodynamics
Qt Interval
Toxicology
Torsade-de-pointes
Activated-charcoal
Healthy-subjects
State
Metabolites
Clearance
Impact
Safety
Drugs
Age
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2007 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 16:58:14 EST