Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite-Resolution for Clinical Development.
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Zheng J, Xin Y, Zhang J, Subramanian R, Murray BP, Whitney JA, Warr MR, Ling J, Moorehead L, Kwan E, Hemenway J, Smith BJ, Silverman JA
Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite-Resolution for Clinical Development.
Drug Metab Dispos. 2018 Mar;46(3):237-247. doi: 10.1124/dmd.117.078899. Epub 2018 Jan 8.
- PubMed ID
- 29311136 [ View in PubMed]
- Abstract
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [(14)C]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 [(14)C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [(14)C]MMB-derived radioactivity was detectable in blood for
