title: Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans.
abstract: The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [(14)C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t(1/2) of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono- and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.
authors.affiliation: Departments of Drug Metabolism and Biopharmaceutics, Incyte Corporation, Wilmington, Delaware, USA. ashilling@incyte.com
authors.forename: Adam D
authors.initials: AD
authors.lastname: Shilling
authors.forename: Frank M
authors.initials: FM
authors.lastname: Nedza
authors.forename: Thomas
authors.initials: T
authors.lastname: Emm
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.forename: Edward
authors.initials: E
authors.lastname: McKeever
authors.forename: Naresh
authors.initials: N
authors.lastname: Punwani
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Argyrios
authors.initials: A
authors.lastname: Arvanitis
authors.forename: Laurine G
authors.initials: LG
authors.lastname: Galya
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Stacey
authors.initials: S
authors.lastname: Shepard
authors.forename: James
authors.initials: J
authors.lastname: Rodgers
authors.forename: Tai-Yuen
authors.initials: TY
authors.lastname: Yue
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D009570:Nitriles; D011720:Pyrazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2