Migraine Treatment Zavegepant Shows No Meaningful Impact on Oral Contraceptive Exposure

In a phase 1 study published in Headache, investigators reported that multiple-dose intranasal zavegepant (Zavzpret; Pfizer), a calcitonin gene-related peptide receptor (CGRP) antagonist approved by the FDA for acute migraine treatment, did not meaningfully alter the pharmacokinetics of a single-dose oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy adult women.¹

The open-label, fixed-sequence study assessed whether zavegepant would affect exposure levels of ethinyl estradiol and levonorgestrel (EE-LNG) when taken together. All told, the data showed less than a 12% increase in exposure, which researchers noted was not considered clinically meaningful. Comparison ratios for EE were 109.9% (AUC_0-inf) and 110.2% (C_max), and for LNG were 107.0% (AUC_0-inf) and 108.8% (C_max), all in the 90% confidence intervals.

The single-center study included healthy, nonsmoking women aged 18 years to 45 years split into 2 treatment periods. In the first treatment phase, participants received a single oral dose of EE-LNG (0.02–0.10 mg) on day 1 while the second treatment period comprised a regimen of 20 mg of intranasal zavegepant daily from days 1 to 5—administered as 10 mg per nostril separated by 1 hour—and another single oral dose of EE-LNG on day 2, following the first 10 mg zavegepant dose.

Conducted by lead author Rajinder Bhardwaj, PhD, senior director of clinical pharmacology and translational medicine at Certara, and colleagues, pharmacokinetic measurements were taken for EE-LNG concentrations on day 1 and day 2, and for zavegepant on day 2. The noncompartmental pharmacokinetic analysis included parameters such as C_max, AUC_0-t, and AUC_0-inf. Overall, the pharmacokinetic and safety analysis sets included 23 and 26 participants, respectively.

No deaths or serious adverse events were reported in this phase 1 study of healthy adult women. One participant discontinued after a single dose of EE-LNG because of a COVID-19 infection. All 26 participants (100%) experienced at least 1 treatment-emergent adverse event (TEAE), including 25 of 25 (100%) during co-administration of EE-LNG and intranasal zavegepant, 11 of 26 (42%) after EE-LNG alone, and 24 of 25 (96%) following zavegepant alone.

READ MORE: Post Hoc Analysis of ADVANCE Trial Reveals Atogepant Improves Functional Outcomes in Migraine

The most frequently reported TEAEs were dysgeusia (96%), throat irritation (42%), headache (39%), nasal discomfort (27%), pharyngeal paresthesia (19%), and nausea (15%). Of the 248 TEAEs reported, 239 were considered related to study drugs, with most linked to intranasal zavegepant. All events were mild or moderate in severity, and all resolved by the study’s end except for mild cases of menstrual disorder and alopecia in 1 participant.

All told, this fixed-sequence, 2-period study design allowed for the assessment of potential drug interactions after steady-state exposure to intranasal zavegepant was achieved. Although fixed-sequence designs can introduce period effects, single doses of EE-LNG were used in line with FDA guidance. Multiple doses of zavegepant were chosen to reflect a worst-case scenario for CYP enzyme inhibition. The study did not assess the impact of steady-state EE-LNG on zavegepant; however, zavegepant's pharmacokinetics remained consistent with prior data.

Building on recent safety data around zavegepant’s coadministration profile, a recently published phase 1 study of healthy volunteers showed that treatment with zavegepant 20 mg nasal spray coadministered with sumatriptan 12 mg subcutaneous (SC) injection, resulted in no significant pharmacodynamic (PD) or pharmacokinetic (PK) interactions compared with sumatriptan alone. Investigators concluded that concomitant administration of these 2 therapies was well tolerated, with a favorable safety profile.²

The single-center, partially blind, placebo-controlled study included 42 healthy volunteers who received sumatriptan 2 x 6 mg SC injections (1 hr apart) on day 1, followed by a 6:1 randomization to zavegepant 2 x 10 mg nasal spray or placebo on days 2 and 3. On day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. Led by senior author Jing Liu, PhD, a senior director of clinical pharmacology at Pfizer, the study’s main goal was to evaluate the drug-drug interactions between the 2 agents, as triptans like sumatriptan have been known to be associated with a risk of increased blood pressure (BP).

When comparing the coadministration of the 2 drugs on day 4 to sumatriptan alone on day 1, there were no difference in the mean arterial pressure (MAP). Similarly, there were no differences in diastolic BP (DBP) and systolic BP (SBP) during that time. The mean time-weighted average (TWA) for MAP remained consistent after sumatriptan and zavegepant coadministration on Day 4 (87.2) compared to sumatriptan alone on Day 1 (86.9), with similar values observed across zavegepant, placebo, and sumatriptan + placebo treatments, ranging from 81.0 to 85.1.

REFERENCES
1. Bhardwaj R, Collins J, Madonia J, Matschke K, Bertz R, Liu J. Effects of multiple-dose administration of zavegepant nasal spray on the single-dose pharmacokinetics of ethinyl estradiol-levonorgestrel. Headache. 2025;65(1):14-23. doi:10.1111/head.14863
2. Bhardwaj R, Donohue MK, Madonia J, et al. Assessment of pharmacokinetic and pharmacodynamic interactions between zavegepant and sumatriptan: A phase 1, randomized, placebo-controlled study in healthy adults. Headache. 2025;65(2):315-325. doi:10.1111/head.14853