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

Abstract

Background: PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects.

Methods: Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD.

Results: PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (Tmax of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased Cmax by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9-fold to 1.3-fold for Cmax. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ≥ 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed.

Conclusions: PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases.

Trial registration: Clinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015.

Keywords: IRAK4; Pharmacodynamic; Pharmacokinetic.

Conflict of interest statement

All authors are current or past employees of Pfizer Inc. and hold shares in Pfizer Inc.

Figures

Fig. 1

Design and PF-06650833 final dosing scheme in a study 1 (SAD) and b study 2 (MAD). aPK 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. bDose administered after consumption of a high-fat breakfast meal. cAlternate IR formulation. dCohort 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. BID twice daily; IR immediate-release: MAD multiple ascending doses; MR modified-release; PK pharmacokinetics; QD once daily; QID four times per day; SAD single ascending doses; TID three times per day

Fig. 2

Median plasma concentration-time profile of SAD of PF-06650833 a IR doses ≤ 100 mg, b IR doses > 100 mg, and c MR formulations. All doses were administered orally under fasting conditions (overnight fast of ≥ 10 h) unless otherwise indicated. Fed doses were administered after consumption of a high-fat breakfast meal. Summary statistics were calculated by setting concentration values below the LLOQ to 0. The LLOQ was 0.0500 ng/mL. IR immediate-release; LLOQ lower limit of quantification; MR modified-release; SAD single ascending doses

Fig. 3

Median plasma concentration-time profile of MAD of PF-06650833 IR and MR formulations at steady state on day 14. Time post-dose refers to the first morning dose on day 14. Day 14 data for cohort 5 (IR 1000 mg QID) were not available due to premature discontinuation of this cohort on day 9. Summary statistics were calculated by setting concentration values BLQ to 0. The LLOQ was 0.0500 ng/mL, except four pre-dose samples with LLOQ of 0.100 ng/mL. All doses were administered orally under fed conditions (standard meal). BID twice daily; BLQ below lower limit of quantification; IR immediate-release; LLOQ lower limit of quantification; MAD multiple ascending doses; MR modified-release; QD once daily; QID four times per day; TID three times per day

Fig. 4

Geometric mean (90% CI) change from baseline in serum hsCRP following MAD of IR and MR PF-06650833 formulations. Baseline was defined as the last pre-dose measurement taken on day 1. Time post-dose refers to the first morning dose. Values below the LLOQ were set to half of the LLOQ in the calculation. The LLOQ of hsCRP was 0.015 mg/dL. Unplanned readings and early withdrawal readings are excluded. The dosing in 1000 mg QID dose group was stopped by the sponsor after the second dose on day 9, and the subjects had their follow-up visits 2 days (approximately 43 h) and 13 days (approximately 310 h) after the last dose on day 9. BID twice daily; CI confidence interval; D day; h hour; hsCRP high-sensitivity C-reactive protein; IR immediate-release; LLOQ lower limit of quantification; MAD multiple ascending doses