Risk assessment in extrapolation of pharmacokinetics from preclinical data to humans.

Prediction of pharmacokinetics in humans is essential for translating preclinical data to humans and planning safe and efficient clinical studies. The performance of various methods in extrapolation of preclinical pharmacokinetic data to humans is usually benchmarked by the fraction of predictions falling within a predefined interval that is centred on the value observed clinically. Recently, such an approach was used to compare physiologically based pharmacokinetic (PBPK) modelling and allometry in predicting the pharmacokinetics of a set of compounds in humans. Here, we present an analysis of the same dataset, focusing on predictions falling outside such a relatively narrow and centrally located interval. These are the main risk determinants in extrapolation of preclinical pharmacokinetic data to humans and should therefore be thoroughly understood in a risk mitigation approach to the design of early-phase human studies.