Translation of drug-induced QTc prolongation in early drug development.
Vincent F.S. Dubois1, Meriel Shearer1, Anne Chain1, Piet van de Graaf2, Mark Holbrook2, Derek Leishman3, David Gallacher4, Meindert Danhof1, Oscar Della Pasqua1,5
1 Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, The Netherlands 2 Pfizer, Sandwich Research Unit, UK 3 Global Safety Pharmacology, Eli Lilly, USA 4 Cardiovascular Safety, Johnson & Johnson, Belgium 5 Clinical Pharmacology, Modelling & Simulation, GlaxoSmithKline, UK
Objectives: Assessment of the propensity of non-antiarrhythmic drugs in prolonging QT/QTc interval is critical for the progression of compounds into clinical development. Given the similarities in QTc response between dogs and humans, dogs are often used in pre-clinical CV safety studies . However, itís unclear how the changes in QTc interval in dogs can be translated into risk of QTc prolongation in humans. We suggest the use of Bayesian hierarchical modelling taking into account the concentration-effect (PKPD) relationship to predict drug effects in terms of the probability associated with QTc prolongation. The objective of our investigation was to characterise the PKPD relationships and translational gaps across species following the administration of three compounds with known QT-prolonging effects.
Methods:Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials following administration of moxifloxacin, d,l-sotalol and cisapride were used. First, pharmacokinetic models were developed in NONMEM VI v2.0 to derive drug concentrations at the time of each QT measurement. The PKPD model used to describe QT prolongation was based on a previous analysis of sotalol data by Krudys et al. A threshold of >10msec was used to explore the probability of prolongation following drug administration. The relevance of a model-based approach is further illustrated by simulations using preclinical parameter estimates to predict drug effect in humans following administration of the three compounds. PKPD modelling was performed using WinBUGS v1.4.3.
Results:Preliminary results from experiments in a limited number of animals suggest that PKPD relationships in the dog are predictive of the risk for QTc prolongation in humans. Probability curves based on dog data showed that QTc prolongation >10 msec could be predicted for drug concentrations associated with therapeutic dose range in humans.
Conclusions:: The liability for QTc prolongation can be expressed in terms of the probability associated with an increase >10 msec. This allows direct comparison between pre-clinical and clinical data. These findings also indicate that PKPD parameter estimates in conscious dogs may be used as basis for the prediction of drug-induced QTc prolongation in humans. However, characterisation of pharmacokinetics and protein binding in both species is critical for the assessment and interpretation of the actual risk in humans.
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