Pharmacokinetics and Safety of Momelotinib in Subjects With Hepatic or Renal Impairment

Abstract

Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open-label, parallel-group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200-mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least-squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration-time curve from time 0 to ∞ [AUC ] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUC was increased (GMR, 197%; 90%CI, 129%-301%), and M21 AUC was decreased (GMR, 52%; 90%CI, 34%-79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced.

Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non–Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure

“…The safety profile of momelotinib and trametinib at the doses tested were generally consistent with the known safety profile of each agent. The PK analysis was generally comparable with previous evaluations 11 and showed that maximum momelotinib plasma concentrations were approximately 300 ng/mL (equal to 0.72 μmol/L), which is below levels required to inhibit TBK1 kinase activity. 3 …”

Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma

“…PK analysis was generally comparable to prior evaluations [16, 20]. Maximum momelotinib plasma concentrations were approximately 300 ng/mL (equal to 0.72 μmol/L).…”

A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer

“…Erlotinib PK were not affected by momelotinib, whereas the momelotinib maximum concentration and exposure were higher than previously reported with a prolonged terminal elimination half-life [35]. In addition, C max and AUC tau of the major metabolite GS-644603 were several-fold lower than previously reported [35][36][37][38]. Erlotinib is a potent inhibitor of aldehyde oxidase [39], which is necessary for the formation of GS-644603 [40], perhaps accounting for the low levels of GS-644603 observed in this study.…”