A Pooled Analysis of Pharmacokinetic Variability Information for Common Probe Substrates Used in Drug-Drug Interaction Studies.

Sample size estimates for drug-drug interaction (DDI) studies are often based on variability information from the literature or from historical studies, but small sample sizes in these sources may limit the precision of the estimates obtained. This project aimed to create an intra-subject variability library of the pharmacokinetic (PK) exposure parameters, area under the curve, and maximum plasma concentration, for probes commonly used in DDI studies. Data from 66 individual DDI studies in healthy subjects relating to 18 common probe substrates were pooled to increase the effective sample size for the identified probes by 1.5- to 9-fold, with corresponding improvements in precision of the intra-subject PK variability estimates in this library. These improved variability estimates will allow better assessment of the sample sizes needed for DDI studies in future.

Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants.

PURPOSE: BMS-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. METHODS: In 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. RESULTS: BMS-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. CONCLUSIONS: BMS-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.