Population Pharmacokinetics and Exposure–Response Analyses of Momelotinib, Its Active Metabolite (M21), and Total Active Moiety in Myelofibrosis

Momelotinib, a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor, is approved for the treatment of myelofibrosis with anemia. These analyses characterized the population pharmacokinetics of momelotinib and its active metabolite M21 following administration of the commercial tablet formulation in patients with myelofibrosis from phase II/III trials and other participants from phase I trials (N = 661). Predicted covariate effects on momelotinib, M21, and total active moiety (TAM)-representing the combined potency-weighted exposures of momelotinib and M21-exposures following 200-mg once-daily dosing were evaluated using a simulation-based approach. Using sequential modeling, momelotinib was described by a two-compartment model with six transit absorption compartments and first-order elimination, and M21 by a two-compartment model with first-order elimination. Hepatic function, concomitant CYP3A4 inducers, and concomitant OATP1B1/1B3 inhibitors were significant momelotinib covariates, while baseline creatinine clearance and hepatic function were significant M21 covariates, with cumulative effects on TAM. Exposure-response relationships between the average TAM concentration under actual dosing and key efficacy and safety end points were assessed using data from the 24-week randomized period of three phase III trials in patients with myelofibrosis (N = 417). After relevant covariate adjustment, significant positive relationships were identified with spleen volume reduction and transfusion independence (the latter specifically in JAK inhibitor-experienced patients), but not symptom improvement. Greater TAM exposure was significantly associated with lower odds of grade 3/4 anemia and higher odds of any-grade peripheral neuropathy, although the latter was infrequently observed in phase III trials. There was no significant relationship with grade ≥ 3 thrombocytopenia or any-grade diarrhea.