Global Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts.
Global Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts
Drug Metab Dispos. 2022 Jul;50(7):980-988. doi: 10.1124/dmd.122.000836. Epub 2022 May 11.
Quantitative assessment of hepatic clearance (CL) of drugs is critical to accurately predict human dose and drug-drug interaction (DDI) liabilities. This is challenging for drugs that involve complex transporter-enzyme interplay. In this study, we demonstrate this interplay in the CL and DDI effect in the presence of CYP3A4 perpetrator for pevonedistat using both the conventional clearance model (CCM) and the extended clearance model (ECM). In vitro metabolism and hepatocyte uptake data showed that pevonedistat is actively transported into the liver via multiple uptake transporters and metabolized predominantly by CYP3A4 (88%). The active uptake clearance (CL) and passive diffusion clearance (CL) were 21 and 8.7 ml/min/kg, respectively. The CL was underpredicted as Empirical Scaling Factor of 13 was needed to recover the in vivo plasma clearance (CL). Both CCM and ECM predicted CL of pevonedistat reasonably well (predicted CL of 30.8 (CCM) and 32.1 (ECM) versus observed CL of 32.2 ml/min/kg). However, both systemic and liver exposures in the presence of itraconazole were well predicted by ECM but not by CCM (predicted pevonedistat plasma area under the concentration-time curve ratio (AUCR) 2.73 (CCM) and 1.23 (ECM))., The ECM prediction is in accordance with the observed clinical DDI data (observed plasma AUCR of 1.14) that showed CYP3A4 inhibition did not alter pevonedistat exposure systemically, although ECM predicted liver AUCR of 2.85. Collectively, these data indicated that the hepatic uptake is the rate-determining step in the CL of pevonedistat and are consistent with the lack of systemic clinical DDI with itraconazole. SIGNIFICANCE STATEMENT: In this study, we successfully demonstrated that the hepatic uptake is the rate-determining step in the CL of pevonedistat. Both the conventional and extended clearance models predict CL of pevonedistat well however, only the ECM accurately predicted DDI effect in the presence of itraconazole, thus providing further evidence for the lack of DDI with CYP3A4 perpetrators for drugs that involve complex transporter-enzyme interplay as there are currently not many examples in the literature except prototypical OATP substrate drugs.
定量评估药物的肝清除率（CL）对于准确预测人体剂量和药物相互作用（DDI）的风险至关重要。对于涉及复杂转运体-酶相互作用的药物，这是一项具有挑战性的任务。在这项研究中，我们使用传统清除模型（CCM）和扩展清除模型（ECM），展示了在 CYP3A4 诱导剂存在的情况下，pevonedistat 的 CL 和 DDI 效应中的这种相互作用。体外代谢和肝细胞摄取数据表明，pevonedistat 通过多种摄取转运体主动转运至肝脏，并主要被 CYP3A4（88%）代谢。主动摄取清除率（CL）和被动扩散清除率（CL）分别为 21 和 8.7 ml/min/kg。需要使用经验性缩放因子 13 才能恢复体内血浆清除率（CL），因此 CL 被低估了。CCM 和 ECM 均能较好地预测 pevonedistat 的 CL（预测 CL 分别为 30.8（CCM）和 32.1（ECM）与观察到的 32.2 ml/min/kg）。然而，在酮康唑存在的情况下，CCM 未能预测系统和肝脏暴露，而 ECM 可以预测（预测的 pevonedistat 血浆浓度-时间曲线下面积比（AUCR）分别为 2.73（CCM）和 1.23（ECM））。ECM 预测与观察到的临床 DDI 数据一致（观察到的血浆 AUCR 为 1.14），表明 CYP3A4 抑制不会改变 pevonedistat 的全身暴露，尽管 ECM 预测肝脏 AUCR 为 2.85。总的来说，这些数据表明，肝脏摄取是 pevonedistat CL 的限速步骤，与酮康唑的系统临床 DDI 缺乏一致。意义陈述：在这项研究中，我们成功地证明了肝脏摄取是 pevonedistat CL 的限速步骤。CCM 和 ECM 都能很好地预测 pevonedistat 的 CL，但是只有 ECM 准确预测了酮康唑存在时的 DDI 效应，因此为涉及复杂转运体-酶相互作用的药物与 CYP3A4 诱导剂之间缺乏 DDI 提供了进一步的证据，因为目前除了典型的 OATP 底物药物外，文献中没有太多的例子。
