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

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 [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 [C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [C]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 rat or dog, the rodent and nonrodent 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 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…This JAK1/2 (as well as activin A receptor type 1, ACVR1) dual inhibitor also demonstrated rapid absorption after oral dosing. Interestingly, its main metabolite, a morpholino lactam, is also active against JAK1/2 and ACVR1 in vitro, suggesting a significant contribution of this morpholino metabolite to the pharmacological effect of the parent drug …”

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

“…( B ) Graphs depicting cell viability of OV-054 DSRCT (blue) and the two Ewing sarcoma models (gray), upon a 5-day incubation with different drug concentrations (µM). Known plasma concentrations are shown with the vertical dashed line [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy

“…The Mann-Whitney U test (Graphpad Prism 7) was performed to study whether IKBKE and TBK1 median expression were significantly different between sample groups. (11) lymphoma_DLBCL (18) lymphoma_Hodgkin (12) B-cell_ALL ( 15) liver ( 28) breast ( 58) leukemia_other ( 1) urinary_tract ( 27) CML ( 15) colorectal ( 61) mesothelioma (11) glioma ( 62) lung_NSC ( 131) meningioma ( 3) stomach (38) ovary ( 51) other ( 15) melanoma ( 61) esophagus (25) thyroid (12) osteosarcoma (10) soft_tissue ( 21) chondrosarcoma ( 4) medulloblastoma ( 4) prostate ( 7) Ewings_Sarcoma ( 12) neuroblastoma ( 17) lung_small_cell (53) upper_aerodigestive (32) lymphoma_other (28) AML (34) T-cell_ALL ( 16) endometrium ( 27) bile_duct ( 8) pancreas ( 44) multiple_myeloma ( 30) kidney (34)…”

“…24 This matches the effective concentrations of momelotinib in the IKBKE-sensitive AML cells. In addition, concentrations in the range of 2 mM can be achieved in humans, 25 so again, the concentrations used have the potential for clinical relevance.…”