TY  - JOUR
JF  - Pharmacology Research & Perspectives
A1  - Dubois, VFS
A1  - Danhof, M
A1  - Della Pasqua, O
ID  - discovery1529314
N2  - Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modelling can be used to assess the probability of QTc interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate non-clinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of prodromic drug effects in humans. ECG and drug concentration data from safety pharmacology study in dogs were analysed using nonlinear mixed effects modelling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration vs. time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QTc interval of ? 5 and ?10 ms. Point estimates for the slope in dogs suggested low probability of ?10 ms prolongation in humans. However, an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals the drug-specific parameter in dogs. In addition, our analysis show that understanding of interspecies differences in drug disposition is required to accurately predict the QT prolonging effects in humans. Extrapolation of the effects of parent compound may not be sufficient to describe the increase in QT interval observed after administration of methadone in humans. Assessment of the contribution of enantioselective metabolism and active metabolites is critical.
UR  - http://dx.doi.org/10.1002/prp2.284
N1  - © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
IS  - 1
TI  - Characterising QT interval prolongation in early clinical development: a case study with methadone
Y1  - 2017/01/24/
AV  - public
VL  - 5
ER  -