Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite—Resolution for Clinical Development

• DOI: 10.1124/dmd.117.078899
• Publication Date: 2018-01-08T14:15:21Z
• Authors: Jim Zheng; Yan Xin; Jingyu Zhang; Raju Subramanian; Bernard P. Murray; J. Andrew Whitney; Matthew R. Warr; John Ling; Lisa Moorehead; Ellen Kwan; Jeffrey Hemenway; Bill J. Smith; Jeffrey A. Silverman
• Keywords: Active metabolite

Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and activin A receptor type 1 (ACVR1), is in clinical development for the treatment myeloproliferative neoplasms. The pharmacokinetics disposition [¹⁴C]MMB were characterized single-dose, human mass-balance study. Metabolism pharmacologic activity key metabolites elucidated multiple vitro vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% radioactivity recovered, primarily feces urine as secondary route. Mean blood-to-plasma [¹⁴C] area under plasma concentration-time curve ratio 0.72, suggesting low association blood cells. [¹⁴C]MMB-derived detectable ≤48 hours, no irreversible binding or its metabolites. major circulating metabolite, M21 (a morpholino lactam), potent JAK1/2 ACVR1 vitro. Estimation pharmacological index suggests contributes significantly to inhibition both ACVR1. observed disproportionately higher amounts than rat dog, rodent nonrodent species used general nonclinical safety assessment this molecule. This discrepancy resolved additional studies wherein drug-drug interactions further characterized. metabolism mediated by cytochrome P450 enzymes, whereas formation involved initial oxidation morpholine ring followed via aldehyde oxidase.