Evaluate multiple-dose itraconazole, a strong cytochrome (CYP)3A4 and P-glycoprotein (P-gp) inhibitor, on single-dose zavegepant (oral and nasal spray) pharmacokinetics (PK) in healthy adults and assess safety and tolerability.

Zavegepant (BHV-3500) is a high-affinity, selective, small-molecule CGRP antagonist in development for migraine, metabolized by CYP3A4, and a P-gp substrate.

Eighteen participants (median [range] age 35.5 [22-51] years, majority male, white, and not Hispanic or Latino) received ≥1 dose of zavegepant. Itraconazole co-administration with zavegepant nasal spray had no clinically relevant impact on zavegepant concentrations, while increasing oral zavegepant AUC and C_max by 59% and 77%, respectively. Exposure comparison ratios (90% confidence intervals) for zavegepant nasal spray were 101.66% (82.06%,125.93%) and 87.73% (63.95%, 120.35%) for AUC_0-inf  and C_max, respectively, and those for oral zavegepant were 158.56% (115.84%, 217.02%) and 177.09% (108.48%, 289.12%) for AUC_0-inf and C_max, respectively. Seventeen (94.4%) participants experienced ≥1 treatment-emergent adverse event (AE), with no deaths, serious AEs, or AEs leading to discontinuation.

No clinically relevant change in zavegepant nasal spray exposure following administration with itraconazole suggests that CYP3A4 doesn’t play a major role in zavegepant clearance, and clinically significant drug interactions with strong CYP3A4 inhibitors are unlikely. Increased exposure following oral zavegepant with itraconazole is likely due to itraconazole inhibition of gastrointestinal P-gp. Overall, all treatments were well tolerated and exhibited a favorable safety profile.