Mass Balance and Metabolism of 14C‐Atogepant in Healthy Male Participants: Findings of a Phase 1 Clinical Trial

ABSTRACT Atogepant, a calcitonin gene‐related peptide (CGRP) receptor antagonist, is approved for the preventive treatment of migraine in adults. This open‐label, phase 1 study examined radiolabeled atogepant (14C‐atogepant) metabolism, elimination, and mass balance after a single dose (50 mg, ~200 μCi) in healthy adult males. Blood, urine, and feces were collected ≤ 28 days for atogepant, metabolite, and radioactivity level measurement. Six participants were enrolled (mean age: 33.3 years; body mass index: 28.8 kg/m2); five completed the study (one withdrew on Day 7 for family emergency). For atogepant, median time to maximum concentration (Tmax) was 1 h and mean terminal elimination half‐life (T1/2) was 18.5 h; for total radioactivity, Tmax was 1.5 h and mean T1/2 was 11.6 h. Unchanged atogepant was the major circulating species in plasma (mean atogepant/total radioactivity area under the curve ratio: ~0.75). In the 14 days after dosing, ~81% and ~8% of the radioactive dose were recovered in feces and urine, respectively. In feces, parent drug (unabsorbed drug, biliary excretion, and/or intestinal secretion) accounted for 42% of administered radioactivity. At least 11 metabolites were identified in feces, and each represented < 10% of administered radioactivity. In plasma, atogepant and metabolite M23 were the only radiometric peaks detected. Metabolite M23, tentatively characterized as dioxygenated methylated glucuronide of atogepant, represented ~15% of plasma radioactivity and was short‐lived. There were no treatment‐emergent adverse events or clinically meaningful changes in laboratory values, vital signs, or the electrocardiogram.