Abstract

Quantitative assessment of hepatic clearance (CL_H) 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_H 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_act,inf) and passive diffusion clearance (CL_diff,inf) were 21 and 8.7 mL/minute/kg, respectively. The CL_act,inf was underpredicted as Empirical Scaling Factor of 13 was needed to recover the in vivo plasma clearance (CL_plasma). Both CCM and ECM predicted CL_plasma of pevonedistat reasonably well (predicted CL_plasma of 30.8 (CCM) and 32.1 (ECM) versus observed CL_plasma of 32.2 ml/minute/kg). However, both systemic and liver exposures in the presence of itraconazole were well predicted by ECM but not by CCM (predicted pevonedistat plasma 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_H 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_H of pevonedistat. Both the conventional and extended clearance models predict CL_plasma 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.