title: A randomized dose-escalation study to assess the safety, tolerability, and pharmacokinetics of ruxolitinib (INC424) in healthy Japanese volunteers.
abstract: Ruxolitinib (INC424), a potent and selective oral Janus kinase 1 and 2 inhibitor, was recently approved by the US food and drug administration for the treatment of intermediate or high-risk myelofibrosis. The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been extensively evaluated in healthy subjects and patients. The present study is the first to investigate the PK and tolerability of ruxolitinib in the Japanese population. Forty subjects were randomized to receive single (10-100 mg) and multiple (10 and 25 mg every 12 h) doses of ruxolitinib or placebo. Cohorts were sequentially enrolled based on the outcome of safety assessments. Ruxolitinib was rapidly absorbed, and its exposure increased dose proportionally up to 100 mg. The half-life of ruxolitinib was approximately 3 h, and drug accumulation was not observed after repeated dosing at a 12-h dosing interval. Decreasing absolute neutrophil counts were observed in five Japanese subjects treated once (100 mg, n = 1) or twice (10 mg, n = 3; 25 mg, n = 1) daily. These events were manageable and reversible upon drug discontinuation. Orally administered ruxolitinib was well tolerated in healthy Japanese volunteers. There were no apparent differences in the safety or PK of ruxolitinib between Japanese and non-Japanese subjects.
authors: Medical Co. LTA, Sumida Hospital, 29-1, Honjo 1-Cyome, Sumida-ku, Tokyo, 130-0004, Japan. yoichiro-ogama@lta-med.com
authors: Yoichiro
authors: Y
authors: Ogama
authors: Tomoko
authors: T
authors: Mineyama
authors: Asuka
authors: A
authors: Yamamoto
authors: Margaret
authors: M
authors: Woo
authors: Naomi
authors: N
authors: Shimada
authors: Taro
authors: T
authors: Amagasaki
authors: Kazuto
authors: K
authors: Natsume
mesh_terms: D000328:Adult; D044466:Asian People; D015331:Cohort Studies; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D007564:Japan; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D055728:Primary Myelofibrosis / Q000097:blood / Q000188:drug therapy; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib
references: Blood. 2010 Aug 12;116(6):988-92
references: 20404132
references: Leukemia. 2010 Apr;24(4):859-60
references: 20111067
references: Cancer Cell. 2005 Apr;7(4):387-97
references: 15837627
references: Genes Cancer. 2010 Oct;1(10):979-93
references: 21442038
references: Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H2954-60
references: 11087252
references: Clin Pharmacol Ther. 2001 May;69(5):333-9
references: 11372001
references: J Clin Pharmacol. 2004 Oct;44(10):1083-105
references: 15342610
references: Nat Genet. 2009 Apr;41(4):455-9
references: 19287384
references: Semin Radiat Oncol. 2003 Jul;13(3):176-81
references: 12903007
references: Blood. 2010 Apr 15;115(15):3109-17
references: 20130243
references: Lancet. 2005 Mar 19-25;365(9464):1054-61
references: 15781101
references: Immunol Rev. 2009 Mar;228(1):273-87
references: 19290934
references: Haematologica. 2008 May;93(5):787-8
references: 18450736
references: Leuk Lymphoma. 2008 Oct;49(10):1907-15
references: 18720212
references: Int J Lab Hematol. 2010 Aug 1;32(4):381-6
references: 20331763
references: Blood. 2008 Sep 15;112(6):2190-8
references: 18779404
references: J Clin Pharmacol. 2012 Jun;52(6):809-18
references: 21602517
references: J Clin Pharmacol. 2011 Dec;51(12):1644-54
references: 21257798
references: N Engl J Med. 2010 Sep 16;363(12):1117-27
references: 20843246
references: Br J Clin Pharmacol. 1996 Jan;41(1):69-72
references: 8824695
references: Hematology. 2009 Dec;14(6):323-30
references: 19941738