Comparative Bioavailability of Single-Dose Zavegepant Nasal Spray During and Between Migraine Attacks: a Phase 1, Randomized, Open-Label, Fixed-Sequence, 2-Period Study

INTRODUCTION: Zavegepant nasal spray is a high affinity, selective, small molecule calcitonin gene-related peptide receptor antagonist in development for the treatment of migraine. Delayed absorption and reduced exposure during migraine attacks has been observed with orally administered antimigraine drugs, including triptans, and it is possible that the pharmacokinetics (PK) of zavegepant could be altered during migraine attacks. OBJECTIVES: Compare the rate and extent of absorption of zavegepant 10 mg (therapeutic) or 20 mg (supratherapeutic) nasal spray during and between migraine attacks and assess the relationship between zavegepant exposure and therapeutic response. METHODS: This was a multicenter, open-label, randomized, single-dose, 2-period, fixed-sequence, comparative bioavailability study. Participants were randomized to a single dose of zavegepant 10 mg or 20 mg nasal spray. In Period 1, participants administered zavegepant during a migraine attack; in Period 2, after a washout of 4–60 days, they administered zavegepant during a nonmigraine period. Blood samples for PK analysis were collected for ≤24 hours postdose. A population PK model (N=9 Phase 1 studies, including this one) was used to generate post hoc exposure parameters (AUC0-24h and Cmax). Post hoc exposure parameters were plotted against migraine pain intensity and functional disability scores at 2 and 24 hours postdose. RESULTS: The study population (N=39) had a median (range) age of 48 (23–71) years and was 71.8% female and 100% white, with a median body mass index of 27.2 kg/m2. Mean zavegepant plasma concentrations were lower during a migraine attack than between attacks at most time points (Figure, A). During a migraine attack, exposure following zavegepant 10 mg was ∼17% lower for Cmax and 10% lower for AUC0-inf than exposure between attacks; exposure was 28% lower for Cmax and 27% lower for AUC0-inf after a 20 mg dose. Zavegepant exposure comparison ratios (90% CIs) after a 10 mg dose were 82.76% (60.49%, 113.24%) for Cmax and 90.06% (70.23%, 115.48%) for AUC0-inf; after a 20 mg dose, they were 72.46% (57.86%, 90.75%) for Cmax and 73.42% (58.81%, 91.67%) for AUC0-inf. Median Tmax was 0.5 hours in both periods. The final population PK model showed that attack status was not a significant covariate. Pain free, pain relief, and functional disability scores at 2 and 24 hours postdose were similar based on the population PK-derived AUC0-24 h and Cmax. (Figure, B). CONCLUSION: Zavegepant exposure was reduced by ∼17% for Cmax and 10% for AUC0-inf during a migraine attack versus between attacks following the therapeutic 10 mg dose; there was no effect on zavegepant Tmax. No exposure-related differences on efficacy endpoints were observed at 2 or 24 hours postdose at a dose range of 10 to 20 mg.