Safety tolerability pharmacokinetics and pharmacodynamics of PF-06650833 a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in single and multiple ascending dose randomized phase 1 studies in healthy subjects

摘要

Design and PF-06650833 final dosing scheme in study 1 (SAD) and study 2 (MAD). PK and PD sampling time was up to 96 h for cohorts 1 and 2. Subjects in cohorts 3 and 4 were followed up to day 21 of the final period to better characterize the terminal phase, given the potentially long elimination half-life based on emerging data. Dose administered after consumption of a high-fat breakfast meal. Alternate IR formulation. Cohort 3 consisted of only four periods, and cohort 4 consisted of only two periods that were separated by 14 days, in order to maintain the overall predicted exposure in an individual subject to ≤ 28 days. In study 1, within each period, 8 subjects were randomized to receive PF-06650833 and 2 subjects were randomized to receive placebo. All subjects within a cohort received one or more doses of PF-06650833 and/or placebo. Doses were escalated sequentially within each period, based on evaluation of ≥ 48 h of safety and tolerability for all subjects and ≥ 8 h of PK data for at least 6 subjects receiving PF-06650833 and 1 subject receiving placebo. All doses were administered orally under fasting conditions (overnight fast of ≥ 10 h) unless otherwise indicated. In study 2, within each cohort, eight subjects were planned to receive PF-06650833 and 2 subjects were planned to receive placebo. All doses were administered orally under standard (not high-fat) meal, fed conditions. QD doses were 24 h apart, BID doses were 12 h apart, TID doses were 8 h apart, and QID doses were 6 h apart. When dosing in the fed condition, the morning and evening doses were administered within 5 min of completing the standard meal. twice daily; immediate-release: multiple ascending doses; modified-release; pharmacokinetics; once daily; four times per day; single ascending doses; three times per day