Physiologically based Pharmacokinetic (PBPK) Modelling of Cisplatin in Rats and Humans

Abstract

The physiologically based pharmacokinetic (PBPK) modelling has been accepted as one of the most effective mechanistic techniques to analyze pharmacokinetics (PK) of drugs in the drug development process. Its effectiveness in predicting the PK of drugs is important not only to the current drug development industry but also to potential growth of the pharmaceutical industry as it helps resolve ethical challenges.

The PK of cisplatin as an anticancer drug, and its metabolic disposition are investigated by proposing a PBPK modelling framework. A plausible PBPK model is developed to test and validate its predictive utility for extrapolation to other species with the drug. Building and testing a PBPK modelling workflow for translating from rat to human PK scenarios for cisplatin is particularly emphasized. Moreover, this workflow may be helpful to studying and understanding the PK of cisplatin analogues in future studies.

In this thesis, the PK of cisplatin is quantitatively studied by employing the PBPK modelling technique, and the modality of interspecies extrapolation from rat models to human models is then tested. As the metabolic mechanism of cisplatin is not evidently revealed, several assumptions have been made to successfully construct the PBPK model which would closely reproduce observed PK data of cisplatin for rats as well as for humans. Based on these assumptions, several parameters which define cisplatin ADME in an organism are reasonably selected. These parameters are optimized based on observed rat PK data by using a numerical optimization process. The PBPK model constructed based on the rat PK data is then evaluated by means of validating the optimized values of the parameters through comparing the PK simulations with other observed PK data for rats. Lastly, the validity of the model for the predictive performance on humans is assessed by translating the model into a human model and evaluating it based on observed PK data for humans.