Abstract
PurposeBMS-986142 is an oral, small-molecule reversible inhibitor of Bruton’s tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination.MethodsIn a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5–900 mg) or multiple doses (25–350 mg, once daily for 14 days). In a drug–drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants.ResultsBMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX.ConclusionsBMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.
Highlights
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting 0.5–1.0% of the population in industrialized countries [1]
A total of 80 participants were enrolled in study 1: 48 patients in the single ascending dose (SAD) group (6 participants in each BMS-986142 dose group, 12 in the placebo group), and 32 in the multiple ascending dose (MAD) group (6 participants in each BMS-986142 group, 8 in the placebo group)
In the study 1 SAD group, 22 adverse events (AEs) were reported in 8 participants (22.2%) treated with BMS-986142, and 6 AEs were reported by 2 participants (16.7%) treated with the placebo (Table 1, Online Resource 4)
Summary
Eligible participants were confined to the clinical facility (WCCT Global, LLC, Cypress, CA) the day before dosing (day −1) and randomized to receive SAD or MAD treatment under fasting conditions for 10 h. In the SAD group, eight healthy non-Japanese participants were assigned to each of up to six sequential dose panels (single oral doses of 5, 15, 50, 100, 300, and 900 mg BMS-986142) or placebo. In the MAD group, eight healthy non-Japanese participants were assigned to each of four sequential dose panels (daily oral doses of 25, 75, 200, and 350 mg BMS-986142) or placebo. Participants were randomized in a 3:1 ratio to receive once-daily (QD) doses of BMS-986142 or placebo from day 1 to day 14 (Online Resource 1). Blood samples for the measurement of BMS-986142 were collected up to 168 h after dosing of BMS-986142 on day 1 for participants in SAD. The result for each sample was expressed as a percentage inhibition relative to the pre-dose sample
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