A phase 1 study to investigate the absorption, distribution, metabolism and excretion of brepocitinib in healthy males using a ¹⁴C‐microdose approach

Abstract

AimsBrepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa) using a 14C microtracer approach.MethodsThis was a phase 1 open‐label, nonrandomized, fixed sequence, two‐period, single‐dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 μg dose of 14C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed.ResultsSix participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported.ConclusionIntestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug‐related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor.NCT: NCT03770039.