To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults. Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug-drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings. This was a Phase 1, single-center, partially blind, randomized, placebo-controlled, single-arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre-specified time points. Forty-two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty-one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time-weighted average (TWA) of mean arterial pressure (MAP [sumatriptan+ zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: -0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: -0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: -0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC0-inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC0-24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. Overall, 90% (38/42) of participants experienced ≥ 1 treatment-emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated. Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults.