Deconvoluting zavegepant drug–drug interactions: A phase I study to evaluate the effects of rifampin and itraconazole on zavegepant pharmacokinetics

Zavegepant is a calcitonin gene-related peptide receptor antagonist for acute migraine treatment. This Phase I, open-label, fixed-sequence study evaluated the effects of itraconazole (a strong cytochrome P450 3A4 [CYP3A4] and P-glycoprotein [P-gp] inhibitor) on the pharmacokinetics of intranasal/oral zavegepant and the effects of rifampin (a strong inducer of CYP3A4 and P-gp; and an inhibitor of organic anion transporting polypeptide 1B3 [OATP1B3]) on oral zavegepant in healthy participants. In the intranasal/oral zavegepant-itraconazole cohort, participants received a single 10-mg dose of zavegepant nasal spray on Day 1, followed by oral zavegepant (50 mg) on Day 3. Itraconazole 200 mg once daily was administered from Days 4 to 12. On Day 7 zavegepant nasal spray and on Day 11 oral zavegepant were coadministered with itraconazole. In the oral zavegepant-rifampin cohort, participants received oral zavegepant (100 mg) on Day 1, rifampin 600 mg once daily on Days 2-10, and rifampin with zavegepant on Day 11. No significant change in zavegepant exposure was observed following coadministration of itraconazole with zavegepant nasal spray. For oral zavegepant coadministered with itraconazole, the area under the curve from 0 to infinity (AUC_0-inf) and the maximum observed concentration (C_max) of oral zavegepant increased by 59% and 77%, respectively. For oral zavegepant coadministered with rifampin, the AUC_0-inf and C_max of oral zavegepant increased by approximately 2.3- and 2.2-fold, respectively. These results suggest that OATP1B3 and intestinal P-gp are the more prominent pathways, as opposed to CYP3A4, for a zavegepant drug-drug interaction. Coadministration of OATP1B3 inhibitors with zavegepant nasal spray should be avoided.