(R)-2-((2-(1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxylmetabolite of VX-509, which is involved in clinically significant TDIbased DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.

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The ability to predict human liver-to-plasma unbound partition coefficient (K puu ) is important to estimate unbound liver concentration for drugs that are substrates of hepatic organic anion-transporting peptide (OATP) transporters with asymmetric distribution into the liver relative to plasma. Herein, we explored the utility of PXB chimeric mice with humanized liver that are highly repopulated with human hepatocytes to predict human hepatic disposition of OATP substrates, including rosuvastatin, pravastatin, pitavastatin, valsartan, and repaglinide. In vitro total uptake clearance and transporter-mediated active uptake clearance in C57 mouse hepatocytes were greater than in PXB chimeric mouse hepatocytes for rosuvastatin, pravastatin, pitavastatin, and valsartan. Consistent with in vitro uptake data, enhanced hepatic uptake and resulting total systemic clearance were observed with the above four compounds in severely compromised immune-deficient (SCID) control mice compared with the PXB chimeric mice, which suggest that mouse has a stronger transporter-mediated hepatic uptake than human. In vivo liver-to-plasma K puu from PXB chimeric and SCID control mice were also compared, and rosuvastatin and pravastatin K puu in SCID mice were more than 10-fold higher than that in PXB chimeric mice, whereas pitavastatin, valsartan, and repaglinide K puu in SCID mice were comparable with K puu in PXB chimeric mice. Finally, PXB chimeric mouse liver-to-plasma K puu values were compared with the reported human K puu , and a good correlation was observed as the PXB K puu vales were within 3-fold of human K puu . Our results indicate that PXB mice could be a useful tool to delineate hepatic uptake and enable prediction of human liver-toplasma K puu of hepatic uptake transporter substrates. SIGNIFICANCE STATEMENTWe evaluated PXB mouse with humanized liver for its ability to predict human liver disposition of five organic anion-transporting polypeptide transporter substrates. Both in vitro and in vivo data suggest that mouse liver has a stronger transporter-mediated hepatic uptake than the humanized liver in PXB mouse. More importantly, PXB liver-to-plasma unbound partition coefficient (K puu ) values were compared with the reported human K puu , and a good correlation was observed. PXB mice could be a useful tool to project human liver-to-plasma K puu of hepatic uptake transporter substrates.The work was supported by Vertex Pharmaceutical Company Limited and Chimeric Mouse with Humanized Liver (CMHL) Consortium. Y.M. is an employee of PhoenixBio Co., Ltd., Hiroshima, Japan. He provided PXB mice but did not have any additional role in conducting the experiment, performing the data analysis, or preparing the manuscript. All other authors (B.