Chemical formula: C₂₃H₂₂N₆O₂ Molecular mass: 414.18 g/mol PubChem compound: 25062766
Momelotinib and its major human circulating metabolite (M21), are inhibitors of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F, which contribute to signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. JAK1 and JAK2 recruit and activate STAT (signal transducer and activator of transcription) proteins that control gene transcription impacting inflammation, haematopoiesis, and immune regulation. Myelofibrosis is a myeloproliferative neoplasm associated with constitutive activation and dysregulated JAK signalling that contributes to elevated inflammation and hyperactivation of activin A receptor type 1 (ACVR1), also known as activin receptor-like kinase 2 (ALK-2). Additionally, momelotinib and M21 are direct inhibitors of ACVR1, which further down regulates liver hepcidin expression resulting in increased iron availability and red blood cell production. Momelotinib and M21 potentially inhibit additional kinases, such as other JAK family members, inhibitor of κB kinase (IKK), interleukin-1 receptor-associated kinase 1 (IRAK1), and others.
Momelotinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis and inhibits hepcidin. Maximal inhibition of STAT3 phosphorylation occurred 2 hours after momelotinib dosing with inhibition persisting for at least 6 hours. An acute and sustained reduction of circulating hepcidin was observed for the duration of the 24-week study, associated with increased iron levels and haemoglobin, following administration of momelotinib to patients with myelofibrosis.
Momelotinib is rapidly absorbed after oral administration with the maximal plasma concentration (Cmax) achieved within 3 hours post-dose, with plasma exposures increased in a less than dose-proportional manner, especially at doses above 200 mg. In a clinical study, at the dose of 200 mg once daily at steady state, the mean momelotinib Cmax (% CV) is 479 ng/mL (61%) and AUCtau is 3288 ng×h/mL (60%) in patients with myelofibrosis.
Following low-fat and high-fat meals in healthy volunteers, the Cmax of momelotinib was 38% and 28% higher, respectively, and the AUC was 16% and 28% higher, respectively, as compared with those under fasted conditions. These changes in exposure were not clinically meaningful.
Plasma protein binding of momelotinib is approximately 91% in humans. Based on population pharmacokinetics, the mean apparent volume of distribution of momelotinib at steady-state was 984 L in patients with myelofibrosis receiving momelotinib 200 mg once daily suggesting extensive tissue distribution.
Based on in vitro assessment, momelotinib is metabolised by multiple CYP enzymes (including CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP1A2). Generation of the active metabolite M21, involves biotransformation by CYP enzymes followed by metabolism by aldehyde oxidase.
Following an oral dose of momelotinib 200 mg, the mean terminal half-life (t½) of momelotinib was approximately 4 to 8 hours; the half-life of M21 was similar. Based on a clinical study, the apparent total clearance (CL/F) of momelotinib was 103 L/h in patients with myelofibrosis.
Momelotinib is mainly eliminated through metabolism and then excreted to faeces. Following a single oral dose of [14C]-labelled momelotinib in healthy male subjects, 69% of radioactivity was excreted in the faeces (13% of dose as unchanged momelotinib), and 28% in the urine (<1% of dose as unchanged momelotinib).
Effect of momelotinib on UDP-glucuronosyltransferase (UGT):
Momelotinib is an inhibitor of UGT1A1 and UGT1A9 at clinically relevant concentrations, but the clinical relevance is unknown. Momelotinib and its major circulating metabolite are not inhibitors of the other isoforms (UGT1A3/4/6 and 2B7) at clinically relevant concentrations.
Effect of momelotinib on CYP450 enzymes:
At clinically relevant concentrations neither momelotinib nor the major circulating metabolite, M21, represent a risk of inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
Effect of momelotinib on drug transporters:
In vitro data indicates that momelotinib inhibits OCT1 and the active metabolite, M21, inhibits MATE1 at clinically relevant concentrations. Neither momelotinib nor M21 have been evaluated for MATE2-K inhibition.
In vitro data indicate that neither momelotinib nor its major metabolite, M21, inhibits the following transporters at clinically relevant concentrations: organic anion transporter 1 and 3 (OAT1, OAT3) and OCT2.
Effect of momelotinib on hormonal contraceptives:
Multiple doses of momelotinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. However, a risk for induction of other pregnane X receptor (PXR) regulated enzymes apart from CYP3A4 cannot be completely excluded and the effectiveness of concomitant administration of oral contraceptives may be reduced.
Gender and race (White vs Asian) do not have a clinically relevant effect on the pharmacokinetics of momelotinib based on exposure (AUC) data in healthy subjects. Exploratory results of population pharmacokinetics analysis in patients did not show any effects of age, weight, or gender on momelotinib pharmacokinetics.
Momelotinib AUC increased by 8% and 97% in subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively, compared to subjects with normal hepatic function.
Momelotinib was not carcinogenic in mice and rats at exposures up to 12 and 17 times the clinical exposure level at 200 mg once daily based on combined momelotinib and the active major human metabolite, M21 (minimally produced in mice, rats and rabbits), AUC.
Momelotinib was not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for gene mutations and chromosomal aberrations.
In fertility studies, momelotinib was administered orally to male and female rats. In males, momelotinib reduced sperm concentration and motility and reduced testes and seminal vesicle weights at doses of 25 mg/kg/day and greater (exposures 13-times the recommended dose of 200 mg daily based on combined momelotinib and M21 AUC) resulting in reduced fertility at 68 mg/kg/day.
Observations in females included reduced ovarian function at 68 mg/kg/day and decreased number of pregnancies, increased pre- and post-implantation loss with total litter loss in most animals at 25 and 68 mg/kg/day. Exposures at the no adverse effect level in male and female rats at 5 mg/kg/day were approximately 3 times the recommended dose of 200 mg daily (based on combined momelotinib and M21 AUC).
In animal reproduction studies, oral administration of momelotinib to pregnant rats during the period of organogenesis caused maternal toxicity at 12 mg/kg/day and was associated with embryonic death, visceral malformation, and decreased foetal weights; skeletal variations were observed at 6 and 12 mg/kg/day and (approximately 3.5-fold the recommended dose of 200 mg daily based on combined momelotinib and M21 AUC). There were no developmental effects observed at 2 mg/kg/day at exposures equivalent to the recommended dose of 200 mg (based on combined momelotinib and M21 AUC).
In pregnant rabbits, oral administration of momelotinib during the period of organogenesis caused severe maternal toxicity and evidence of embryo-foetal toxicity (decreased foetal weight, delayed bone ossification, and abortion) at 60 mg/kg/day at less than the exposure equivalent to the recommended dose of 200 mg (based on combined momelotinib and M21 AUC).
In an oral pre- and post-natal development study, rats received oral administration of momelotinib from gestation to end of lactation. Evidence of maternal toxicity, embryo-lethality, and decreased birth weights were observed at 6 and 12 mg/kg/day. Pup survival was significantly reduced at 12 mg/kg/day from birth to Day 4 of lactation at exposures similar to or less than the exposure at the recommended dose (based on combined momelotinib and M21 AUC) and was therefore considered a direct effect of momelotinib via exposure through the milk.
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