Drug Interaction Report

MONITOR: Coadministration with inducers of the CYP450 3A4 isoenzyme and/or P-glycoprotein efflux transporter may decrease the plasma concentrations of maraviroc, which is a substrate of both. According to the product labeling, administration of maraviroc (100 mg twice a day) with the potent CYP450 3A4/P-glycoprotein inducer rifampin (600 mg once a day) reduced the mean maraviroc peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 66%, 63% and 78%, respectively, compared to administration alone. When the same dosage of maraviroc was administered with efavirenz (600 mg once a day), maraviroc Cmax, AUC, and Cmin decreased by approximately 50% each. In contrast, maraviroc Cmax increased by 25% and AUC increased by 153% during coadministration with efavirenz (600 mg once a day) plus the potent CYP450 3A4 inhibitors lopinavir/ritonavir (400 mg/100 mg twice a day). An even greater increase of 2.3-fold in Cmax and 5-fold in AUC was observed during coadministration of maraviroc (300 mg twice a day) and efavirenz plus saquinavir/ritonavir (1000 mg/100 mg twice a day).

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if maraviroc is used with CYP450 3A4 and/or P-glycoprotein inducers. A dosage adjustment for maraviroc may be necessary if an interaction is suspected. Some authorities recommend a dosage of 300 mg twice daily when administered concomitantly with rifabutin and tipranavir/ritonavir or fosamprenavir/ritonavir. However, if a potent CYP450 3A4 inhibitor such as itraconazole, ketoconazole, delavirdine, clarithromycin, telithromycin, nefazodone, or any protease inhibitor (except tipranavir/ritonavir or fosamprenavir/ritonavir) is also used with the inducer, then maraviroc dosage should be reduced to 150 mg twice daily.

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.

Administration with food may reduce the bioavailability of maraviroc. According to the product labeling, coadministration of a 300 mg dose of maraviroc with a high-fat breakfast reduced maraviroc peak plasma concentration (Cmax) and systemic exposure (AUC) by 33% in healthy volunteers. However, no food restrictions were used in the clinical studies that demonstrated the safety and efficacy of maraviroc. Therefore, maraviroc can be taken with or without food at the recommended dosage.