In vitro to human in vivo translation – pharmacokinetics and pharmacodynamics of quinidine

Abstract

The translational sciences aim to transfer results from basic research to the treatment of animals or patients. One of the approaches that could be utilized to achieve this goal is the in vitro-in vivo extrapolation (IVIVE) of pharmacokinetic (PK) and pharmacodynamic (PD) properties using in silico methods. Such methodology, if properly applied, could help substantially reduce the use of animals in pre-clinical research. Here, quinidine was chosen as an example of a drug with cardiac effects and results of nine published clinical studies describing its PK (plasma concentration) and PD (QTcB/ΔQTcB) effects were mimicked by combination of the IVIVE platform Simcyp (pharmacokinetics prediction) with the ToxComp (cardiac effect prediction) system, based exclusively on in vitro data. The results show that reliable QT prediction is possible using the mechanistic IVIVE of the PK and PD effects. This can be considered a proof-of-concept that also could be applied as a drug safety evaluation procedure.