Absorption, metabolism, and excretion of single-dose oral [14C]camizestrant in healthy human female participants

Camizestrant is a next-generation selective estrogen receptor degrader and complete estrogen receptor antagonist and is being evaluated for the treatment of patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. This Phase 1, single-center, single-period, non-randomized, open-label study sought to determine the mass balance recovery of camizestrant and conduct metabolite profiling and structural identification. Routes of elimination, safety, and tolerability were secondary objectives. Six healthy female postmenopausal participants (median age 60.5 years, range: 59–69) were administered a single dose of 75 mg oral [ 14 C]camizestrant (solution) following an overnight fast. Blood, urine, and fecal samples were collected at protocol-defined intervals until mass balance criteria were met. By the end of the sampling period (432 hours postdose), 82% of the administered total radioactivity was recovered in excreta (urine, 16.8%; feces, 65.2%). The amount of radioactivity excreted in the feces in the first 24 hours was minimal, providing evidence that camizestrant absorption was high; most of the administered total radioactivity in feces was recovered between 24–192 hours postdose, suggesting biliary elimination. Unchanged camizestrant represented 13.6% of the total drug-related material in plasma. Of the 11 identified metabolites in plasma, an N-glucuronide conjugate of camizestrant (M4) and an N-glucuronide of an acid metabolite (M14) were the most abundant (20.1% and 11.2%, respectively). Thirteen metabolites were identified in urine (M4 most abundant; 2.3% of total radioactive dose). Eight metabolites were identified in feces (oxidative defluorinated alcohol metabolite [M1] was most abundant; 14.5% of total radioactive dose); unchanged camizestrant represented 14.5% of the total radioactive dose in feces, with in vitro data supporting unchanged camizestrant being likely due, in part, to hydrolyzed M4.