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Updated: Oct 7, 2025
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
A pharmacokinetic-pharmacodynamic model based on multi-organ-on-a-chip for drug-drug interaction studies
Kenta Shinha1, Wataru Nihei, Tatsuto Ono1
1Department of Mechanical Engineering, School of Engineering, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan.
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.
Insights
Organ-on-a-chip (OoC) models can predict drug-drug interactions (DDI). A multi-organ-on-a-chip system combined with a pharmacokinetic-pharmacodynamic model accurately estimated DDI for anticancer drugs.
Area of Science:
- Pharmacology
- Drug Discovery
- Biotechnology
Background:
- Drug-drug interactions (DDI) pose risks in drug discovery due to poor pharmacokinetic understanding.
- Organ-on-a-chip (OoC) technology is an in vitro model for drug efficacy and toxicity but not yet applied to DDI studies.
Purpose of the Study:
- To evaluate the applicability of organ-on-a-chip technologies for drug-drug interaction (DDI) studies.
- To develop and validate a multi-organ-on-a-chip (MOoC) model integrated with a pharmacokinetic-pharmacodynamic (PK-PD) model for DDI assessment.
Main Methods:
- A MOoC model was constructed with liver (metabolism) and cancer (drug target) components.
- An anticancer prodrug, CPT-11, was used to assess metabolite efficacy.
- The inhibitory effects of simvastatin and ritonavir on CPT-11 metabolism were evaluated to assess DDI.
Main Results:
- The MOoC model successfully evaluated the efficacy of CPT-11 metabolites.
- DDI estimation using the MOoC and PK-PD model showed similar results to concomitant administration experiments.
- The combined PK-PD model and MOoC approach proved useful for predicting DDI.
Conclusions:
- Organ-on-a-chip technologies, particularly the developed MOoC system, can be effectively applied to drug-drug interaction (DDI) studies.
- The integration of PK-PD modeling with MOoC facilitates a better understanding of pharmacokinetic mechanisms in DDI.
- This approach offers a promising in vitro strategy for predicting DDI during drug development.
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