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-cyclopentylpro-panenitrile (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 investi-gated in healthy human subjects given a single oral 25-mg dose of [14C]INCB018424 as an oral solution. INCB018424 and total radio-activity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t1/2 of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70 % within 24 h post-dose) 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 lo