title: The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers.
abstract: Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1-20 mg and multiple ascending doses of 2-20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼2 L/h. The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.
authors: From Incyte Corporation, Wilmington, DE, USA.
authors: Jack G
authors: JG
authors: Shi
authors: Xuejun
authors: X
authors: Chen
authors: Fiona
authors: F
authors: Lee
authors: Thomas
authors: T
authors: Emm
authors: Peggy A
authors: PA
authors: Scherle
authors: Yvonne
authors: Y
authors: Lo
authors: Naresh
authors: N
authors: Punwani
authors: William V
authors: WV
authors: Williams
authors: Swamy
authors: S
authors: Yeleswaram
mesh_terms: D000293:Adolescent; D000328:Adult; D001384:Azetidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines; D011720:Pyrazoles; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001384:Azetidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; C000596027:baricitinib
keywords: JAK; baricitinib; pharmacodynamics; pharmacokinetics; rheumatoid arthritis