Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of ticagrelor, which is primarily metabolized by the isoenzyme. In 14 healthy volunteers, administration of a single 180 mg oral dose of ticagrelor on day 12 of treatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 14 days) decreased mean ticagrelor peak plasma concentration (Cmax), systemic exposure (AUC) and plasma half-life by 73%, 86% and 67%, respectively, compared to administration of ticagrelor alone. Mean Cmax of the major active metabolite was unchanged in the presence of rifampin, but mean AUC decreased by 46% and plasma half-life by 50%. Inhibition of platelet aggregation (IPA) was also assessed in the study. Mean IPA at 12 hours was 87% with ticagrelor alone versus 63% in combination with rifampin; corresponding values at 24 hours were 70% and 15%, respectively.

MANAGEMENT: Concomitant use of ticagrelor with potent CYP450 3A4 inducers should generally be avoided.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivosidenib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. Pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole, and the moderate inhibitor, fluconazole. When a single 250 mg dose of ivosidenib was administered with itraconazole 200 mg once daily for 18 days, ivosidenib systemic exposure (AUC) increased to 269% of control, with no change in peak plasma concentration (Cmax). Based on physiologically-based pharmacokinetic modeling, coadministration of a 500 mg dose of ivosidenib with fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control, while multiple-dosing of both is predicted to increase ivosidenib steady-state Cmax and AUC to 152% and 190% of control, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to ivosidenib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

GENERALLY AVOID: Coadministration with a high-fat meal may increase the plasma concentrations of ivosidenib. According to the product labeling, administration of a single dose with a high-fat meal (approximately 900 to 1000 calories; 500 to 600 calories in fat, 250 calories in carbohydrate, 150 calories in protein) increased ivosidenib Cmax and AUC by 98% and 25%, respectively, in healthy study subjects.

MANAGEMENT: Ivosidenib may be administered with or without food, but should not be administered with a high-fat meal. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with ivosidenib.