THU0199 PHARMACOKINETICS, SAFETY AND TOLERABILITY OF SINGLE- AND MULTIPLE- DOSE ONCE-DAILY BARICITINIB IN CHINESE HEALTHY VOLUNTEERS – A RANDOMIZED PLACEBO-CONTROLLED STUDY

Abstract

Background: Baricitinib, an oral selective inhibitor of JAK1 and JAK2, is efficacious in patients with moderately to severely active rheumatoid arthritis and an inadequate response to methotrexate. Objectives: To evaluate the pharmacokinetics (PK), safety and tolerability of baricitinib when given orally as single and multiple doses in healthy Chinese subjects. Methods: This was a single-site, subject- and investigator-blinded, randomized, and placebo-controlled study (NCT02758613) conducted from 04 May 2016 to 25 July 2016. Eligible subjects were healthy Chinese adults (≥18 years) with a body mass index of 19.0 to 24.0 kg/m2 (inclusive). Subjects received a once daily dose (QD) of baricitinib 2, 4 or 10 mg or placebo on Day 1 (single dose) and Days 4 through 10 for 7 consecutive days (multiple dose). Safety assessments were performed throughout the treatment period. Plasma PK samples were collected up to 48 hours after dosing on Days 1 and 10, with predose samples collected prior to dosing on Day 1 and Days 4 through 10. PK parameters were calculated using noncompartmental analysis. Results: A total of 33 healthy volunteers were randomized and received at least 1 dose of study drug (placebo, n=8; baricitinib 2 mg, n=8; baricitinib 4 mg, n=9; baricitinib 10 mg, n=8). All subjects were male and the mean age was 27.8 years. After both single- and multiple-dose administration, baricitinib 2 to 10 mg was rapidly absorbed, reaching peak plasma concentrations within 0.5 to 1 hour (median). Plasma concentrations declined rapidly following attainment of peak concentrations, with a mean terminal half-life of 5.7 to 7.3 hours. Steady state plasma concentrations of baricitinib were achieved after the second day of QD dosing, with minimal accumulation of baricitinib in plasma (up to 10%) during 7 days of QD oral doses of 2 to 10 mg baricitinib. Single- and multiple-dose mean values for AUC(0-∞) and Cmax appeared to increase in an approximately dose-proportional manner across the dose range. Overall incidence of treatment-emergent AEs (TEAEs) is 33.3%. All TEAEs reported were mild in severity, with no serious AEs reported and no subjects were withdrawn due to AEs. Although there was an apparent increase in the incidence of drug-related TEAEs over the 2 to 10 mg dose range, the incidence of drug-related TEAEs at the 10 mg dose was comparable to placebo. Conclusion: The PK of baricitinib in Chinese healthy subjects were characterized by rapid absorption and elimination following single and multiple oral doses of up to 10 mg. Systemic exposure to baricitinib increased in an approximately dose-proportional manner following single and multiple doses. Single and multiple oral doses of daily-administered baricitinib up to 10 mg were well tolerated by healthy Chinese subjects. Disclosure of Interests: Xia Zhao: None declared, Christopher Payne Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Feng Wang Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Yiming Cui: None declared