Safety and Pharmacokinetics of Ruxolitinib (INC424) in Healthy Japanese Volunteers: Placebo-Controlled, Double-Blind, Dose-Escalation Phase 1 Study

Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been evaluated in non-Asian healthy subjects. However, its ethnic sensitivity has not been investigated. This is the first study in Japan to evaluate the safety, tolerability, and PK of ruxolitinib in healthy Japanese volunteers.

There were 4 dose cohorts with 10 male subjects in each, 8 randomized to receive ruxolitinib and 2 randomized to receive placebo. In cohort 1 (10 mg) and cohort 2 (25 mg), each subject received a single dose (QD) of ruxolitinib or placebo on day 1 and received twice daily (bid) doses on days 4 through 10. In cohorts 3 and 4, subjects received a single dose of ruxolitinib (50 and 100 mg, respectively) or placebo on day 1. Serial blood samples for PK analysis were collected up to 48 hours post-dose, and ruxolitinib concentrations were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters were derived from individual plasma concentration time data using non-compartmental analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 3.0.

The median age of the 40 enrolled healthy subjects was 27 years. Ruxolitinib was rapidly absorbed (C_max achieved 0.5 hours after dosing), and exposure increased dose proportionally between 10 and 100 mg (Table). Consistent with the half-life of 2–3 hours and a 12-hour dosing interval, drug accumulation was not observed after repeated dosing. These results are similar to those obtained in non-Japanese healthy volunteers (Shi JG, et al. J Clin Pharmacol, May 20, 2011 [epub ahead of print]).

AUC_(0–¥), area under the curve from zero to infinity; C_max, maximum plasma concentration; t_1/2, half-life; CL/F, apparent total body clearance.

Consistent with ruxolitinib's inhibition of the JAK pathway, grade 2 decreases in absolute neutrophil counts were observed in 5 subjects (3 in the 10-mg bid cohort, 1 in the 25-mg bid cohort, and 1 in the 100-mg QD cohort). However, these neutrophil decreases were managed with dose reductions in 2 subjects (1 each in the 10- and 25-mg bid cohorts) or without dose reductions in 3 subjects and rapidly recovered after the last administration of the study drug. Laboratory values showed that a similar decrease in neutrophils was also observed in subjects randomized to placebo. One subject (25-mg bid cohort) experienced a grade 1 increase in alanine aminotransferase 3 days following the last dose. All AEs resolved during the study without any treatment and were not dose dependent.

Orally administered ruxolitinib has a predictable PK and is well tolerated in healthy Japanese volunteers. There are no apparent ethnic differences in the PK of ruxolitinib between Japanese and non-Japanese subjects.

Shimada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Natsume:Novartis Pharma K.K.: Employment.