Giovanni Smania1, Ramona Graf1, Massimo Cella1, Vincent Dubois2, Oscar Della Pasqua1,2
1 Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK. 2 Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
Objectives: Assessment of the propensity of new 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 [1]. However, it is unclear how the changes in QTc interval in dogs can be translated into risk of QTc prolongation in humans. The objective of our investigation was to characterise the PKPD relationships of three new compounds in order to assess the interspecies differences in drug-induced QTc prolongation.
Methods: Pharmacokinetic and pharmacodynamic data from typical cardiovascular safety study experiments in conscious dogs and first time in human trials in healthy subjects were used to evaluate the effects of GSK945237, SB237376 and GSK618334, three new compounds in development. First, drug concentrations at the time of each QT measurement were derived. Concentration-QT interval data were then analysed using a hierarchical PKPD model previously implemented and tested with positive controls, namely moxifloxacin, sotalol and cisapride [2]. A threshold of 10msec was used to explore the probability of QTc interval prolongation at the relevant therapeutic range. Results were compared using model-derived PC50 estimates, i.e., the concentration associated with a probability of 50% increase in QTc interval. Modelling was performed using WinBUGS v1.4.3, whilst R was used for data manipulation, graphical and statistical summaries.
Results: Our analysis showed that GSK945237 does not prolong QTc interval neither in humans nor in dogs, whilst SB237376 shows a weak effect in both species, but does not reach 10ms QTc prolongation at the expected therapeutic range. In contrast to the other two compounds, GSK618334 was found to cause QTc-interval prolongation > 10 msec since the range of concentration needed to achieve it contains the observed Cmax. These findings differed from typically reported results in telemetered dogs, which are often based on nonparametric methods and statistical summaries of the data.
Conclusions: Although no QTc-prolonging effects were observed for GSK945237, the results from the analysis of SB237376 and GSK618334 illustrate the value of a quantitative approach to characterise drug effects in early drug development. Furthermore, our analysis shows that accurate interpretation of pre-clinical findings requires suitable pharmacokinetic sampling and some understanding of expected therapeutic exposure. Based on the data analysed so far, including previously published results, dogs appear to be a suitable, but less sensitive species to the drug-induced QTc-prolonging effects, as compared to humans.
References:
[1] Wang, J et al. (2003). Functional and pharmacological properties of canine ERG potassium channels. Am J Physiol, 284, H256-H267.
[2] ASY Chain , VFS Dubois et al. (2013) Identifying the translational gap in the evaluation of drug-induced QTc-interval prolongation. Brit J Clin Pharmacol, in press.
Reference: PAGE 22 (2013) Abstr 2754 [www.page-meeting.org/?abstract=2754]
Poster: Safety (e.g. QT prolongation)