Published in:
01-04-2007 | Correspondence
Application of pharmacokinetic-pharmacodynamic modeling in management of QT abnormalities after citalopram overdose. Reply to A. Manini
Published in: Intensive Care Medicine | Issue 4/2007
Login to get accessExcerpt
Sir, Manini et al. express concerns about the algorithm that we developed for the management of cardiotoxicity in citalopram overdose. We respond to their comments as follows:
1.
In the algorithm we use “dose estimate” and not “ingested dose”. The difference between the dose amount reported (based on the patient history, tablet counts and other available information) and the dose amount estimated in the modelling ranged from 0 to 75 mg, i.e. the reported dose amount was acceptably reliable [1].
2.
Of the three published cases that the authors quote where patients ingested less than 600 mg [2, 3, 4], two did not have an abnormal QT based on the QT nomogram derived from Fossa et al. [5, 6]. Bazett's correction was used in these two cases despite its known overcorrection in patients with fast heart rates. In the third case, a patient was reported to have sinus tachycardia, but absolute QT and RR was not reported, in addition to an uncertainty in the reported dose [2].
3.
The simulations and algorithm are based on a population pharmacokinetic–pharmacodynamic (PKPD) model of 62 overdose events [1, 6] which estimated the interindividual variability for the pharmacokinetic parameters and the uncertainty in dose amount. It allowed for individual heart rate correction of the QT interval [7] and quantified the effect of patient age and sex on the QT interval [6].
4.
5.
Other factors affecting the metabolism of citalopram. Co-ingestion of drugs known to affect citalopram concentration and the QT interval were considered in the model building, but no influences were found [1, 6]. The didesmethylcitalopram metabolite has indeed been associated with cardiotoxicity in dogs [9]. We explicitly allowed for the effect of slowly eliminated toxic metabolites by implementation of a hypothetical effect compartment [6].