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Metabolism, Excretion, and Pharmacokinetics of [ 14 C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans

2010; American Society for Pharmacology and Experimental Therapeutics; Volume: 38; Issue: 11 Linguagem: Inglês

10.1124/dmd.110.033787

1521-009X

Adam D. Shilling, Frank M. Nedza, Thomas Emm, Sharon Diamond, Edward McKeever, Naresh Punwani, William V. Williams, Argyrios G. Arvanitis, Laurine G. Galya, Mei Li, Stacey Shepard, James D. Rodgers, Tai‐Yuen Yue, Swamy Yeleswaram,

Eosinophilic Disorders and Syndromes

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 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 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.