Anne Chain (1), Meindert Danhof (2), Miriam CJM Sturkenboom (3), Oscar E Della Pasqua (2, 4)
(1) Modeling and Simulations, Merck Research Labs, Rahway, New Jersey, USA (2) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands (3) Department of Medical Informatics and Epidemiology & Biostatistics, Erasmus University Medical Center, The Netherlands (4) Clinical Pharmacology/Modelling and Simulation, GlaxoSmithKline, United Kingdom
Objectives: QT/QTc-interval prolongation continues to be a concern in drug development today. More effort is needed to explain the discrepancies between trial outcomes and real life data from epidemiological studies. The objective of this study is to better translate clinical findings to real life situations and resolve the discrepancies in pre- vs. post-market estimates of QTc-interval prolongation.
Methods: Using d,l-sotalol as a paradigm compound, the gap between clinical trial outcomes and epidemiological observations was identified by simulating the drug-induced effects of a population with the same demographic properties as real life users. Any additional effects were evaluated by calculating the absolute differences in QTc prolongation between taking the drug alone and in conjunction with co-medications and comorbidities using the Rotterdam Study cohort as the reference population. A new mechanism-based tool was developed: QTc (real life population) = baseline + circadian rhythm + drug exposure + effects of co-medications and co-morbidity conditions. Distribution of simulated and observed values were then compared non-parametrically. Finally, the approach was validated using the compound, cisapride.
Results: The weight distribution of the Rotterdam cohort showed that 10.8% of the male and 3.4% of the female population would be excluded from clinical trials. Similarly, 21.9% male and 14.9% female would not be included due to baseline measurements. Relative risks were statistically different (p<0.01) between sotalol users and those without heart failure, hypertension, diabetes and myocardial infarction. The presence of diabetes increased QTc-interval prolongation from 4.0 to 6.5; whilst with myocardial infarction it increased from 3.4 to 15.5. By combining all the causal factors in a single simulation, the distribution of the observed QTc values was confirmed to fall within the simulated distribution. The same results were seen with cisapride users.
Conclusions: The underlying assumption in conducting clinical trials is that findings about drug effect are generalisable to the real life population. However, in the case of sotalol, our results showed that only part of the observed QTc distribution in the real life population could be attributed to the drug effect. The new approach demonstrated and validated here enabled better estimation of the true risk that could mitigate future drug-withdrawal due to cardiovascular safety.
Reference: PAGE 22 (2013) Abstr 2802 [www.page-meeting.org/?abstract=2802]
Poster: Safety (e.g. QT prolongation)