Translating QT interval prolongation from conscious dogs to humans

AIM: Despite screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of pro-arrhythmic activity using a comprehensive in vitro pro-arrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. Here we evaluate the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. METHODS: Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of 9 compounds with varying QT prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymised NCEs) were analysed. Mean slope estimates varied between -0.98 and 6.1 ms/μM in dogs and -10 and 90 ms/μM in humans, indicating a wide range of effects on QT interval. Linear regression techniques were then applied to characterise the correlation between the parameters across species. RESULTS: For compounds without a mixed ion channel block a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x, R(2)  = 0.989).These results show that per unit concentration the drug effect on QT interval in humans is 11.6 fold larger than in dogs. CONCLUSIONS: Together with information about the expected therapeutic exposure, the evidence of a correlation between the compounds-specific parameter in dogs and humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalisability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans

Reflections on the Future of Pharmaceutical Public-Private Partnerships : From Input to Impact

Public Private Partnerships (PPPs) are multiple stakeholder partnerships designed to improve research efficacy. We focus on PPPs in the biomedical/pharmaceutical field, which emerged as a logical result of the open innovation model. Originally, a typical PPP was based on an academic and an industrial pillar, with governmental or other third party funding as an incentive. Over time, other players joined in, often health foundations, patient organizations, and regulatory scientists. This review discusses reasons for initiating a PPP, focusing on precompetitive research. It looks at typical expectations and challenges when starting such an endeavor, the characteristics of PPPs, and approaches to assessing the success of the concept. Finally, four case studies are presented, of PPPs differing in size, geographical spread, and research focus