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The Pharmacokinetics, Pharmacodynamics, and Safety of Orally Dosed INCB018424 Phosphate in Healthy Volunteers
Author(s) -
Shi Jack G.,
Chen Xuejun,
McGee Ryan F.,
Landman Robert R.,
Emm Thomas,
Lo Yvonne,
Scherle Peggy A.,
Punwani Naresh G.,
Williams William V.,
Yeleswaram Swamy
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010389469
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , medicine , bioavailability , tolerability , dosing , volume of distribution , oral administration , adverse effect
INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double‐blind, randomized, and placebo‐controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once‐ and twice‐daily dosing for 10 days. As a Biopharmaceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose‐proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3‐hour plasma half‐life and insignificant accumulation following repeat dosing. A high‐fat meal reduced INCB018424 C max by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.