Combination of a multi-organ microphysiological system (MO–MPS) and a pharmacokinetic–pharmacodynamic (PK–PD) model to evaluate drug–drug interactions (DDI)

Abstract

In the field of drug discovery, the emergence of unexpected toxicity is often a problem resulting from a poor understanding of the pharmacokinetics of drug–drug interactions (DDI). In this context, “organs-on-a-chip” has been proposed as a novel in vitro model to evaluate drug efficacy and toxicity in pharmacology, but it has not yet been applied to DDI research. Here, we aim to first estimate a drug-specific parameter, namely, extraction ratio, using a multi-organ microphysiological system (MO–MPS) and to subsequently evaluate the DDI using a pharmacokinetic–pharmacodynamic (PK–PD) model. For this, we propose a combination of an MO–MPS, with a liver part as a metabolic model and a cancer part as a drug target model, and its corresponding PK–PD model. The results of the DDI effects evaluated, thus, were consistent with those previously reported, confirming the efficacy of the combination of an MPS and a PK–PD model in DDI research. It is possible to evaluate more clearly, the effect of the concomitantly administered drugs on the pharmacokinetic changes occurring in MPS, by evaluating DDI by the PK–PD model, using parameters inferred from the experimental results. Our proposed method could facilitate both, a better understanding of the pharmacokinetic mechanisms with DDI as also the evaluation of organ–organ interactions using multi-organ MPS.