Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

objectiveReported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the in vivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs).

backgroundRimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs.

methodsEach study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4.

resultsMean values of single-dose rimegepant maximum concentration (C

conclusionsBased on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.