Zabedosertib, a novel interleukin-1 receptor-associated kinase-4 inhibitor, shows a favorable pharmacokinetic and safety profile across multiple phase 1 studies.

Introduction: Zabedosertib, the interleukin-1 receptor-associated kinase-4 (IRAK4) inhibitor, is in clinical development as an oral therapeutic for immune-mediated inflammatory diseases and was thoroughly investigated in several phase 1 studies in healthy male volunteers. Methods: Pharmacokinetics, safety, and tolerability of zabedosertib were characterized in two clinical phase 1 studies with single oral doses up to 480 mg and multiple oral doses up to 200 mg twice daily over 10 consecutive days. The absolute oral bioavailability was determined in a third study using the intravenous microtracer methodology. Results: Zabedosertib showed good safety and tolerability without dose-limiting toxicities or severe infections. An under-proportional increase in exposure was observed with increasing dose. The observed mean accumulation ratios for the area under the concentration-time curve of 1.04-1.62 were lower than expected based on the dose-independent terminal half-life of 19-30 h. The absolute oral bioavailability was 74% at a dose of 120 mg. No food effect was observed. The pharmacokinetics could be described with a one-compartmental population-pharmacokinetic model with first-order elimination, dose-dependent bioavailability, and capacity-limited binding in plasma. The estimation of target occupancy, based on Conclusion: Based on the projected target occupancy, favorable pharmacokinetics, and safety profile, as well as on distinct pharmacodynamic effects in a proof-of-mechanism study, zabedosertib 120 mg twice daily was selected for further clinical development in patient studies. Clinical trial registration: https://clinicaltrials.gov/, identifier SAD: NCT03054402, MAD: NCT03493269 (part 1), FE/abs.BA study NCT03244462 (EudraCT numbers: 2016-002668-15, 2017-001817-10, and 2016-004393-18).