Bayesian Population Pharmacokinetic/Pharmacodynamic Modeling to Study the Effect on the Cardiovascular Syndrome of the QTc Interval Prolongation of Non-antiarrhythmic Drugs

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 cardiovascular safety studies. The current regulatory guidelines are based on simple statistical analyses of QT data, thereby ignoring any potential exposure-effect relationship and nonlinearity in the underlying physiological fluctuation in QT values. The objective of this analysis is to adopt a model based approach to assess the QT-prolonging effects in dogs and humans of GSK945237, a new compound under development. Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials following administration of GSK945237 were used. First, pharmacokinetic modelling was applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, which allows discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. Results from this analysis show the drug under investigation is not prone to cause hazardous increases in the QT interval for both humans and dogs. Further, the PKPD model is capable to predict both preclinical and clincal data, suggesting it might be used for future translational research in the field of QT prolongation. Chapter