RT Journal Article SR Electronic T1 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite ─ Resolution for Clinical Development JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.117.078899 DO 10.1124/dmd.117.078899 A1 Jim Zheng A1 Yan Xin A1 Jingyu Zhang A1 Raju Subramanian A1 Bernard P. Murray A1 J. Andrew Whitney A1 Matthew R Warr A1 John Ling A1 Lisa Moorehead A1 Ellen Kwan A1 Jeffrey Hemenway A1 Bill J. Smith A1 Jeffrey A. Silverman YR 2018 UL http://dmd.aspetjournals.org/content/early/2018/01/04/dmd.117.078899.abstract AB Momelotinib (MMB) is a small molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood to plasma [14C] area under the plasma concentration - time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [14C]MMB derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rats or dogs, the rodent and non-rodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 (CYP) enzymes, whereas M21 formation involved initial CYP oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.