Sinusoidal Uptake Determines the Hepatic Clearance of Pevonedistat (TAK-924) as Explained by Extended Clearance Model

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/min/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/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 H of pevonedistat and are consistent with the lack of systemic clinical DDI with itraconazole. SIGNIFICANCE STATEMENTIn 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.

Radiosynthesis and Early Evaluation of a Positron Emission Tomography Imaging Probe [18F]AGAL Targeting Alpha-Galactosidase A Enzyme for Fabry Disease

“…In addition to its low permeability, the AGAL molecule also appears to be a substrate of drug efflux transporters as indicated by its efflux ratio of 12.0, which is high (>2.0) and similar to the positive control pevonedistat [14,15] with an efflux ratio of 18.8. To determine the contribution of efflux transporters to this efflux ratio, the bi-directional permeability of the AGAL molecule was assessed in the presence of the P-glycoprotein (P-gp) inhibitor LY335979, the BCRP inhibitor K0143, and the dual inhibitor elacridar.…”

Sinusoidal Organic Anion-Transporting Polypeptide 1B1/1B3 and Bile Canalicular Multidrug Resistance-Associated Protein 2 Play an Essential Role in the Hepatobiliary Disposition of a Synthetic Cyclic Dinucleotide (STING Agonist)

“…The membrane protein abundance of uptake transporters in human hepatocytes lot 8339 and lot 8350, shown in Tables I, II, III, is adopted from our previous study (21). Additionally, we quantified membrane protein expression of reducedfolate carrier (SLC19A1) in human hepatocytes lot 8339 and 8350.…”

“…* Dose concentraton of d8-TCA and digoxin is normalized to compare their total accumulation with ML00960317 at 2.02 μM ND, not detected (LLOQ, lower limit of quantification = 0.1 pmol/mg protein). *Data is adopted from our recent study(21). # Reduced-folate carrier…”