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

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 [14C]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 [14C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [14C]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.

Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support Dose Selection of Tirabrutinib in Subjects with RA.

Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects.

Filgotinib, a selective inhibitor of Janus kinase 1, is being developed for the treatment of chronic inflammatory diseases. Electrocardiograms evaluated the effect of filgotinib on the corrected QT (QTc) interval in 52 healthy subjects who received each of 4 treatments: filgotinib 200 mg (therapeutic dose), 450 mg (supratherapeutic dose), and placebo, each administered once daily for 7 days, and a single dose of moxifloxacin 400 mg (positive control). Plasma samples were collected for pharmacokinetic analysis. The QTc interval was calculated using Fridericia's correction factor (QTcF) or an individual correction factor (QTcI). The relationship between plasma concentrations of filgotinib and its major metabolite and time-matched, baseline-adjusted, placebo-corrected QTc (ΔΔQTc) was evaluated. Filgotinib did not prolong QTcF or QTcI and using an appropriate mixed-effect model, the upper limit of the 2-sided 90% confidence interval for ΔΔQTc for each filgotinib dose (200 and 450 mg) remained below 10 milliseconds at all postdose time points. There were no clinically relevant relationships between QTc interval and plasma concentrations of filgotinib or its major metabolite. Filgotinib, administered at 200 or 450 mg, was generally well tolerated. Results of this thorough QT study demonstrate that filgotinib and its major metabolite are not associated with QTc interval prolongation.

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

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.