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Abstract Details

Effects of the Strong CYP3A4 and P-glycoprotein Inhibitor Itraconazole on the Pharmacokinetics of Oral and Intranasal Zavegepant
Headache
P9 - Poster Session 9 (5:30 PM-6:30 PM)
2-011

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

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.

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.

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.

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.

Authors/Disclosures
Jing Liu
PRESENTER
Jing Liu has received personal compensation for serving as an employee of Pfizer, Inc.. Jing Liu has stock in Pfizer, Inc. .
Rajinder K. Bhardwaj, PhD (Certara) The institution of Dr. Bhardwaj has received personal compensation in the range of $0-$499 for serving as a Consultant for Certara.
Jo Ann Malatesta (Certara Inc.) Ms. Malatesta has nothing to disclose.
Joseph Stringfellow Joseph Stringfellow has nothing to disclose.
Jennifer Madonia (Biohaven Pharmaceuticals) Jennifer Madonia has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Jennifer Madonia has stock in Biohaven Pharmaceuticals.
Matt Anderson Matt Anderson has received personal compensation for serving as an employee of Certara. An immediate family member of Matt Anderson has received personal compensation for serving as an employee of Bristol Myers Squibb. Matt Anderson has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Certara Strategic Consulting. An immediate family member of Matt Anderson has received stock or an ownership interest from Bristol Myers Squibb.
Beth Morris Beth Morris has received personal compensation for serving as an employee of Biohaven Pharmaceuticals Inc. Beth Morris has received stock or an ownership interest from Biohaven Pharmaceuticals Inc.
Vladimir Coric Vladimir Coric has received personal compensation for serving as an employee of Biohaven. Vladimir Coric has received personal compensation in the range of $1,000,000+ for serving as an officer or member of the Board of Directors for Bioahven. Vladimir Coric has stock in Biohaven. Vladimir Coric has received intellectual property interests from a discovery or technology relating to health care.
Robert Croop, MD Dr. Croop has received personal compensation for serving as an employee of Biohaven Pharmaceuticals, Inc. Dr. Croop has received personal compensation for serving as an employee of Pfizer Inc.. Dr. Croop has stock in Biohaven Pharmaceutical Holding Co Ltd. Dr. Croop has stock in Biohaven Ltd.. Dr. Croop has received intellectual property interests from a discovery or technology relating to health care.
Richard Bertz (Biohaven Pharmaceuticals) Richard Bertz has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Richard Bertz has stock in Biohaven Pharmaceuticals.