Zavegepant (BHV-3500) is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist in development for migraine treatment.
In this phase 1, open-label, single-center, single-period study, subjects received one 15-minute IV infusion of 5 mg [14C]‑zavegepant containing ≤3.6 MBq [14C]. Over a 192-hour sampling period, multiple blood, urine, and fecal samples were collected to evaluate mass balance, pharmacokinetics (using noncompartmental analysis methods), and metabolite profiling and identification (using liquid chromatography radio detection and subsequent high-resolution mass spectrometry where appropriate). Safety assessments included treatment-emergent adverse events (TEAEs), Sheehan Suicidality Tracking Scale (S‑STS), physical examinations, electrocardiograms, and clinical laboratory assessments.
Six healthy male participants (aged 39-60 years, body mass index 23.6-32.0 kg/m2, S-STS score 0) were included. Of all radioactivity administered, 96.6% (range 92.1%-102.4%) was recovered in excreta, primarily in feces (mean 84.9% [range 79.7%-94.0%]). The geometric mean volume of distribution during the terminal phase, total clearance values, and plasma terminal half-life of zavegepant were 129 L, 220 mL/min, and 6.8 hours, respectively. Exposure to zavegepant accounted for ~90% of circulating plasma total reactivity of the area under the curve (time 0 extrapolated to infinity). Profiling identified zavegepant, but no metabolites representing ≥10% of radioactivity. Urine and feces contained 11.1% and 80.5% of the administered zavegepant dose, respectively. Three subjects (50.0%) reported ≥1 TEAE; all were mild and considered unrelated to zavegepant. No clinically significant changes were observed in safety parameters.
An IV infusion of 5 mg [14C]‑zavegepant in healthy men was primarily (>80%) recovered in feces indicating biliary excretion, underwent minimal metabolism, had substantial distribution into tissue, and was safe and well tolerated.