Mass balance and absolute bioavailability of avenciguat ( 14 C) after intravenous or oral administration in healthy male participants

Background Avenciguat, a potent nitric oxide-independent activator of soluble guanylyl cyclase, is being evaluated in chronic kidney disease and systemic sclerosis. We assessed avenciguat absolute bioavailability and mass balance.Research design and methods Open-label Phase 1 trial in healthy men. Doses: Part A, 3 mg [14C]-avenciguat single dose (oral solution); Part B, 3 mg unlabeled avenciguat (tablet) then 30 µg [14C]-avenciguat (intravenous). Primary endpoints: Part A, mass balance and recovery of [14C] radioactivity in excreta; Part B, absolute bioavailability. Safety and pharmacokinetics were evaluated.Results In Part A (N = 6), geometric mean recovery of [14C] radioactivity was 90.0% (range 80.6–96.0%). Elimination was mainly via feces (geometric mean 85.3%; range 76.5–91.3%); urine (4.66%; range 4.10–5.31%). In Part B (N = 6), the absolute bioavailability of avenciguat was 83.0%. In pooled plasma, the predominant drug-related component was avenciguat (mean 86.8%); the acyl glucuronide metabolite represented 5.2% of radioactivity. Drug-related adverse events (AEs) occurred in 33.3% (4/12) of participants, mostly mild, with one moderate presyncope event. No AEs leading to discontinuation were reported.Conclusions Avenciguat was generally well tolerated and was primarily excreted unchanged in feces and minimally excreted in urine. After oral administration, avenciguat has high oral bioavailability.Clinical trial registration ClinicalTrials.gov (NCT05515328)