title: Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants.
abstract: OBJECTIVE
  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.
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA. sunku.lee@bms.com.
authors.forename: Sun Ku
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xing
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Catlett
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Adamczyk
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Griffies
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Ang
authors.initials: A
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Murthy
authors.affiliation: Bristol-Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ, 08540, USA.
authors.forename: Miroslawa
authors.initials: M
authors.lastname: Nowak
mesh_terms: D000293:Adolescent; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D055815:Young Adult; D000099192:CD69 Antigens
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007546:Isoquinolines; D037181:Lectins, C-Type; D008727:Methotrexate; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000099192:CD69 Antigens; C000611973:BMS-986152; C000625949:BTK protein, human
keywords: BMS-986142; Drug–drug interaction; Methotrexate; Pharmacodynamics; Pharmacokinetics; Reversible Bruton’s tyrosine kinase inhibitors