PT  - JOURNAL ARTICLE
AU  - Zheng, Jim
AU  - Xin, Yan
AU  - Zhang, Jingyu
AU  - Subramanian, Raju
AU  - Murray, Bernard P.
AU  - Whitney, J. Andrew
AU  - Warr, Matthew R
AU  - Ling, John
AU  - Moorehead, Lisa
AU  - Kwan, Ellen
AU  - Hemenway, Jeffrey
AU  - Smith, Bill J.
AU  - Silverman, Jeffrey A.
TI  - Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite ─ Resolution for Clinical Development
AID  - 10.1124/dmd.117.078899
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.078899
4099  - http://dmd.aspetjournals.org/content/early/2018/01/04/dmd.117.078899.short
4100  - http://dmd.aspetjournals.org/content/early/2018/01/04/dmd.117.078899.full
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.