A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a (14)C‐Microtracer Approach

Zimlovisertib (PF‐06650833) is a selective, reversible inhibitor of interleukin‐1 receptor‐associated kinase 4 (IRAK4) with anti‐inflammatory effects. This phase 1, open‐label, fixed‐sequence, two‐period, single‐dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a (14)C‐microtracer approach. All six participants received 300 mg (14)C‐zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and (14)C‐zimlovisertib 135 μg intravenously (IV) in Period B. Study objectives included extent and rate of excretion of (14)C‐zimlovisertib, pharmacokinetics, and safety and tolerability of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces was 82.4% ± 6.8% (urine 23.1% ± 12.3%, feces 59.3% ± 9.7%) in Period A. Zimlovisertib was absorbed rapidly following oral administration, with the fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 300‐mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the dose‐normalized area under the concentration–time curve from time 0 to infinity. There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%).