Reverse Translation in PBPK and QSP: Going Backwards in Order to Go Forward With Confidence

Significant events have taken place shaping the recent industrialization of physiologically based pharmacokinetic in vitro-in vivo extrapolation (PBPK-IVIVE) use in drug development. Due to our knowledge gaps about drug-independent systems parameters, there are limitations in the use of purely IVIVE-based (bottom-up) approaches. This has encouraged combining the classical data analysis (top-down) with PBPK-IVIVE-linked models in order to optimize model parameters by taking advantage of observed clinical data. This concept, when initiated after clinical observations, can be viewed as "reverse translation," since it refers back to available systems information preclinical data before trying to describe the observations. This review demonstrates the advantages of such strategies in filling knowledge gaps and discusses the perceived hurdles in widening applications. It is paramount that no clinical data are assessed on their own, but in conjunction with other studies for that drug in different populations and/or other similar drugs in the same population.