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

Maximilian Feldmüller^1*Stefan J Jodl¹Bart Ploeger¹Andrea Wagenfeld¹Herbert Wiesinger¹Frank S Zollmann²Stefan Klein¹Ruiping Zhang³Beate Rohde¹Joachim Höchel¹

• ¹Bayer AG, Berlin, Baden-Württemberg, Germany
• ²Pharma Consult, Berlin, Germany
• ³Bayer HealthCare Co. Ltd., Beijing, China

Introduction:The interleukin-1 receptor-associated kinase-4 (IRAK4) inhibitor zabedosertib 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 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 to 1.62 were lower than expected based on the dose-independent terminal half-life of 19 to 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.Estimation of target occupancy – based on the in vitro potency for inhibition of IL-6 as representative pro-inflammatory cytokine in a human whole blood assay, target residence time and unbound plasma pharmacokinetics – indicated ~80% target occupancy over the dosing interval after the maximum feasible dose of 120 mg twice daily. This dose was the highest dose providing relevant exposure increases.Conclusions: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.