Comparative bioavailability of single-dose zavegepant during and between migraine attacks: A phase 1, randomized, open-label, fixed-sequence, two-period study.

Abstract

Objective: To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non-migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response.

Background: Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine.

Methods: This was a Phase 1, multicenter, open-label, randomized, single-dose, two-period, fixed-sequence, comparative bioavailability study. Participants with a history of 2-8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non-migraine period (Period 2). Blood samples were collected pre-dose and at pre-specified intervals up to 24 h post-dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (C_max), area under plasma concentration-time curve from time zero to infinity (AUC_0-inf), and time of C_max (T_max).

Results: A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5-113.2) for C_max and 90.1% (90% CI 70.2-115.5) for AUC_0-inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9-90.8) for C_max and 73.4% (90% CI 58.8-91.7) for AUC_0-inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6-171.4) for C_max and 157.0% (90% CI 133.6-184.5) for AUC_0-inf. Median T_max was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post-dose and efficacy outcomes.

Conclusion: Zavegepant exposure was comparable during a migraine attack and a non-migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non-migraine periods, there was a less-than-dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median T_max was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non-migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes.