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.
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Acknowledgments
We thank the subjects, doctors, nurses, and staff members who participated in the clinical trial for their excellent cooperation. This study was supported by Novartis Pharmaceuticals Corporation. We thank Jillian Brechbiel, PhD, for providing assistance with medical writing and editing. These services were funded by Novartis Pharmaceuticals Corporation.
Conflict of interest
Margaret Woo is an employee of Novartis Pharmaceuticals Corporation. Naomi Shimada, Taro Amagasaki, and Kazuto Natsume are employees of Novartis Pharma K.K. Yoichiro Ogama, Tomoko Mineyama, and Asuka Yamamoto have no conflicts.
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Ogama, Y., Mineyama, T., Yamamoto, A. et al. A randomized dose-escalation study to assess the safety, tolerability, and pharmacokinetics of ruxolitinib (INC424) in healthy Japanese volunteers. Int J Hematol 97, 351–359 (2013). https://doi.org/10.1007/s12185-013-1280-5
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DOI: https://doi.org/10.1007/s12185-013-1280-5