A pharmacokinetic-pharmacodynamic model based on multi-organ-on-a-chip for drug-drug interaction studies.

Abstract

In drug discovery, the emergence of unexpected toxicity is often a problem resulting from a poor understanding of the pharmacokinetics of drug–drug interactions (DDI). Organ-on-a-chip (OoC) has been proposed as an in vitro model to evaluate drug efficacy and toxicity in pharmacology, but it has not been applied to DDI studies yet. In this study, we aim to evaluate whether organ-on-a-chip technologies can be applied to DDI studies. To assess the usefulness of OoC for DDI studies, we proposed a multi-organ-on-a-chip (MOoC) with a liver part as the metabolic model and a cancer part as the drug target model, and a pharmacokinetic–pharmacodynamic (PK–PD) model describing the MOoC. An anticancer prodrug, CPT-11, was used to evaluate the drug efficacy of the metabolite in the liver part of the MOoC. To evaluate DDI using the MOoC, the inhibitory effect of simvastatin and ritonavir on the metabolism of CPT-11 was tested. The DDI estimation method was evaluated by comparing the results of the concomitant administration experiment using the MOoC and the results of simulation using the proposed PK–PD model with the estimated parameters. The results were similar, suggesting that the combination of the PK–PD model and the MOoC is a useful way to predict DDI. We conclude that OoC technologies could facilitate a better understanding of pharmacokinetic mechanisms with DDI.