Effects of the Strong CYP3A4 and P-glycoprotein Inhibitor Itraconazole on the Pharmacokinetics of Oral and Intranasal Zavegepant
Rajinder Bhardwaj1, Jo Ann Malatesta1, Joseph Stringfellow2, Jennifer Madonia3, Matt Anderson1, Beth Morris3, Vladimir Coric3, Robert Croop3, Richard Bertz3
1Certara USA, 2Navitas Data Sciences, 3Biohaven Pharmaceuticals
Objective:

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.

Background:

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

Design/Methods:
In this Phase 1, single-center, open-label, fixed-sequence, drug-drug interaction study, 18 participants received single zavegepant nasal spray dose (10 mg; 1 spray, 1 nostril) on Day (D) 1 and single oral zavegepant dose (softgel capsule; 50 mg) on D3. On D4-12, participants received itraconazole 200 mg once daily, co-administered with single zavegepant nasal spray dose on D7 and single oral zavegepant dose on D11. Itraconazole effects on zavegepant (oral or nasal spray) PK were evaluated separately using generalized linear modeling procedures in SAS.
Results:

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 Cmax 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 AUC0-inf  and Cmax, respectively, and those for oral zavegepant were 158.56% (115.84%, 217.02%) and 177.09% (108.48%, 289.12%) for AUC0-inf and Cmax, respectively. Seventeen (94.4%) participants experienced ≥1 treatment-emergent adverse event (AE), with no deaths, serious AEs, or AEs leading to discontinuation.

Conclusions:

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.

10.1212/WNL.0000000000203177