Utilization of a Human Liver Tissue Chip for Drug-Metabolizing Enzyme Induction Studies of Perpetrator and Victim Drugs

Abstract

Polypharmacy-related drug-drug interactions (DDIs) are a significant and growing healthcare concern. Increasing number of therapeutic drugs on the market underscores the necessity to accurately assess the new drug combinations during pre-clinical evaluation for DDIs. In vitro primary human hepatocyte (PHH)-only models are commonly used only for perpetrator DDI studies due to their rapid loss of metabolic function. But co-culturing non-human cells with human PHHs can stabilize metabolic activity and be utilized for both perpetrator and victim studies, though this raises concerns about human specificity for accurate clinical assessment. In this study, we evaluated Liver Tissue Chip (LTC) with PHH-only liver microphysiological system (MPS) for DDI induction studies. Liver MPS from three individual donors maintained their functional and metabolic activity for up to 4 weeks demonstrating suitability for long-term pharmacokinetics (PK) studies. The responses to rifampicin induction of three PHH donors were assessed using CYP activity and mRNA changes. Additionally, victim PK studies were conducted with midazolam (high clearance) and alprazolam (low clearance) following rifampicin-mediated induction which resulted in a 2-fold and a 2.6-fold increase in midazolam and alprazolam intrinsic clearance values respectively compared to the untreated liver MPS. We also investigated the induction effects of different dosing regimens of the perpetrator drug (rifampicin) on CYP activity levels, showing minimal variation in the intrinsic clearance of the victim drug (midazolam). This study demonstrates the utility of the LTC for in vitro liver-specific DDI induction studies, providing a translational experimental system to predict clinical clearance values of both perpetrator and victim drugs. SIGNIFICANCE STATEMENTThis study demonstrates the utility of the Liver Tissue Chip (LTC) with primary human hepatocyte (PHH)-only liver microphysiological system (MPS) for drug-drug interaction (DDI) induction studies. This unique in vitro system with continuous recirculation maintains long-term functionality and metabolic activity for up to 4 weeks, enabling the study of perpetrator and victim drug pharmacokinetics, quantification of drug-induced CYP mRNA and activity levels, investigation of patient variability, and ultimately clinical predictions.