Combining the novel all-human co-cultured hepatocytes system with physiologicall...

연구 요약

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.

Drug metabolism and disposition: the biological fate of chemicals 학술지에 발표된 이 연구는 Pugliano A, Ekiciler A, Parrott NJ 외 연구팀이 수행하였습니다.

이 연구는 '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.'에 대한 과학적 분석을 제공합니다.

핵심 내용

Cytochrome P450s (CYPs) 2C subfamily (eg, 2C8, 2C9, and 2C19) and phase II enzymes such as uridine 5'-diphospho-glucuronosyltransferases (UGTs) are increasingly relevant in drug development and key targets for enzymatic induction. However, for these enzymes, weak induction signals in standard in vitro tools, such as sandwich-cultured human hepatocytes, challenge drug-drug interaction (DDI) risk assessment. This study evaluated an all-human hepatocyte coculture system (TruVivo) as a more sensitive model for CYP2Cs and UGT1A1 induction. After treatment of cells with rifampicin, carbamazepine, and phenytoin, we demonstrated robust mRNA and activity-fold-induction exceeding or meeting the 2-fold threshold in the coculture system, allowing for estimation of CYP2Cs and UGT1A1 induction parameters (IndC50, Indmax), unlike sandwich culture. Using TruVivo IndC50, Indmax 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.

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