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Identifying the translational gap in the evaluation of drug‐induced QT c interval prolongation
Author(s) -
Chain Anne S.Y.,
Dubois Vincent F.S.,
Danhof Meindert,
Sturkenboom Miriam C.J.M.,
Della Pasqua Oscar
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12082
Subject(s) - qt interval , prolongation , cisapride , sotalol , moxifloxacin , medicine , pharmacodynamics , drug , pharmacology , pharmacokinetics , long qt syndrome , antibiotics , biology , atrial fibrillation , microbiology and biotechnology
Aims Given the similarities in QT c response between dogs and humans, dogs are used in pre‐clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QT c interval prolongation, namely cisapride, d, l ‐sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A B ayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug‐specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro‐arrhythmic effects of cisapride, d,l‐ sotalol and moxifloxacin both in dogs and in humans. The drug‐specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QT c prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug‐induced QT c prolongation in humans. Furthermore, the risk of QT c prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro‐arrhythmic potential of a molecule.