Zavegepant nasal spray, a CGRP receptor antagonist for migraine, was rapidly absorbed (peak blood levels in ~30 minutes), well tolerated at single doses up to 40 mg and daily doses up to 40 mg, with no drug accumulation or safety concerns in two phase 1 trials.
Peak plasma levels in ~30 minutesZavegepant's rapid nasal absorption is faster than oral CGRP antagonists and offers an on-demand, non-injectable migraine treatment option
What the researchers found
Across both studies (144 total participants), zavegepant nasal spray demonstrated rapid absorption with a median time to peak plasma concentration (Tmax) of approximately 0.54 hours (~32 minutes) after a single 10 mg spray. Drug exposure increased proportionally with dose, and there was no evidence of accumulation with repeated once-daily dosing.
Safety was favorable: in the single-dose study, 26% of zavegepant-treated participants reported adverse events versus 17% on placebo. In the multiple-dose study, 75% of zavegepant participants reported adverse events versus 63% on placebo. Most events were mild and self-resolving. No clinically relevant ECG changes or drug-induced liver injury signals were observed at any dose tested (up to 40 mg single and daily).
Why it matters
CGRP (calcitonin gene-related peptide) is the central target in modern migraine treatment, but most anti-CGRP drugs are injectable antibodies requiring monthly or quarterly administration. Zavegepant's nasal spray delivery offers on-demand treatment with rapid onset — peak levels in 30 minutes is faster than oral medications and comparable to subcutaneous injection. This phase 1 data established the foundational safety and pharmacokinetic profile that enabled zavegepant's eventual FDA approval as the first intranasal CGRP antagonist for acute migraine.
How the study worked
Two single-site, phase 1, randomized, double-blind, placebo-controlled studies in healthy adults. The single ascending dose (SAD) study enrolled 72 participants across nine dose cohorts (0.1-40 mg). The multiple ascending dose (MAD) study enrolled 72 participants across six cohorts (5-40 mg daily). Pharmacokinetic parameters including Tmax, Cmax, and AUC were characterized. Safety assessments included adverse event monitoring, ECG monitoring, and liver function tests.
What this study cannot tell us
Phase 1 studies are designed for safety and pharmacokinetics, not efficacy — these trials could not determine whether zavegepant actually treats migraines. The participants were healthy adults, not migraine patients, so tolerability may differ in the target population. The study periods were relatively short, and very long-term safety data would come from later-phase trials and post-marketing surveillance. Sample sizes of 72 per study are standard for phase 1 but may miss rare adverse events.
How to read the evidence
These are two well-designed phase 1 randomized, double-blind, placebo-controlled trials — the gold standard for early safety and pharmacokinetic assessment. While they don't demonstrate efficacy, the rigorous design and favorable results provided strong foundational data for the drug's subsequent clinical development.
When this study was published
Published in 2025 but describing studies conducted in 2018-2019, this report provides the detailed phase 1 data underlying zavegepant's FDA approval in 2023. The pharmacokinetic and safety profiles described remain the foundational reference for this drug.
The bigger picture
The CGRP pathway has transformed migraine treatment, producing both preventive antibodies (erenumab, fremanezumab, galcanezumab) and acute treatments (rimegepant, ubrogepant, zavegepant). Zavegepant stands out as the only CGRP receptor antagonist delivered as a nasal spray, combining the speed advantage of non-oral delivery with the convenience of a non-injectable route. This phase 1 data was instrumental in the drug's clinical development program, which led to FDA approval in 2023. The expanding CGRP drug class demonstrates the therapeutic power of targeting specific neuropeptide pathways.
Questions still open
- Does the rapid ~30-minute absorption translate to equally rapid migraine pain relief in clinical practice?
- How does nasal congestion during a migraine attack affect zavegepant absorption compared to the healthy adults studied here?
- Could zavegepant nasal spray be used for migraine prevention with daily dosing, given the favorable safety profile observed in the MAD study?
Common questions
What is CGRP and why is blocking it helpful for migraines?
Is zavegepant safe to use regularly for frequent migraines?
Read the original research
Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults from two phase 1 randomized, placebo-controlled trials.
Headache, 65(8), 1331-1343
Citation
Bertz, Richard; Donohue, Mary; Madonia, Jennifer; Bhardwaj, Rajinder; Matschke, Kyle T; Anderson, Matt S; Croop, Robert; Liu, Jing. (2025). Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults from two phase 1 randomized, placebo-controlled trials.. Headache, 65(8), 1331-1343. https://doi.org/10.1111/head.15042