Reply to Dr. Mégarbane et al. regarding “Pharmacokinetic/pharmacodynamic modelling of cardiac toxicity in venlafaxine overdose”

Excerpt

Megarbane et al. suggest in their letter that pharmacokinetic–pharmacodynamic (PKPD) analysis in individual patients is the only way to quantify the time-course of in vivo drug effects in overdose patients. Although the analysis of a single case may provide some information that can be used to generate hypotheses for future studies, it is not possible to gain an understanding of variability within the population or of patient characteristics that may explain some of this variability [1]. In addition, and particularly in the overdose setting, each patient may provide too few observations (sparse data) for the PKPD relationship to be reliably determined in a single patient. We have shown in a population PKPD analysis of citalopram overdoses the time course of the in vivo drug effect (QT prolongation), the relationship of this to the pharmacokinetics of the drug and the effect of activated charcoal on the exposure, and quantified the influence of age and gender on QT effects [2, 3]. We were also able to determine the probability of significant QT prolongation at different dose-exposure levels. None of these findings would have been possible if only data from a single individual had been analyzed. …