Combining the novel all-human co-cultured hepatocytes system with physiologically based pharmacokinetic modeling to assess the translatability of cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase induction data

of these precipitants in physiologically based pharmacokinetic (PBPK) modeling resulted in high predictive accuracy. In rifampicin studies, using TruVivo mRNA-derived data from the most sensitive donor 1 and average parameters across donors, was essential to properly predict in vivo DDI, particularly for object drugs mainly metabolized by CYP2Cs and UGT1A1, or with moderate to low CYP3A4 contribution (fm ≤ 0.5) in multipathway metabolism. For object drugs metabolized by CYP3A4 beyond 2Cs and UGTs, carbamazepine and phenytoin PBPK predictions highlighted the applicability of TruVivo uncalibrated CYP3A4 data for accurate assessment, whereas parameters calibrated against rifampicin showed a conservative trend in estimating DDI. Overall, the all-human coculture system, paired with PBPK, offers a breakthrough for CYP2Cs and UGT1A1 preclinical DDI induction risk assessment. SIGNIFICANCE STATEMENT: Cryopreserved human hepatocytes in sandwich culture show limited sensitivity toward cytochrome P450s 2C and uridine 5' -diphospho-glucuronosyltransferases induction, challenging in vitro-in vivo translation of the drug-drug interaction risk. This study confirms that TruVivo is a more sensitive in vitro model. By using physiologically based pharmacokinetic modeling, we investigated the impact of the measured induction parameters on predictive accuracy, showing TruVivo as a useful tool for cytochrome P450s 2C and uridine 5' -diphospho-glucuronosyltransferases risk assessment.