Drug Interaction Report

MONITOR: Coadministration with inhibitors of the CYP450 3A4 isoenzyme and/or P-glycoprotein efflux transporter may increase 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 inhibitor ketoconazole (400 mg once a day) increased the mean maraviroc peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 3.5- and 5-fold, respectively, compared to administration alone. When the same dosage of maraviroc was administered with ritonavir (100 mg twice a day), maraviroc Cmax increased by nearly 1.3-fold and AUC by 2.6-fold. An even greater increase of nearly 5-fold in Cmax and 10-fold in AUC was observed during coadministration of maraviroc and saquinavir/ritonavir (1000 mg/100 mg twice a day). At 300 mg twice a day, mean maraviroc Cmax increased by approximately 2-fold and AUC by 3.6-fold during coadministration with atazanavir (400 mg once a day). When the same dosage of maraviroc was given with atazanavir/ritonavir (300 mg/100 mg once a day), maraviroc Cmax increased by 2.7-fold and AUC increased by nearly 5-fold. During coadministration with lopinavir/ritonavir (400 mg/100 mg twice a day), maraviroc Cmax and AUC increased by 2-fold and 4-fold, respectively.

MANAGEMENT: Caution is advised when maraviroc is used with inhibitors of CYP450 3A4 and/or P-glycoprotein. Dosage adjustment for maraviroc may be necessary if an interaction is suspected.

GENERALLY AVOID: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of glasdegib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. When glasdegib was coadministered with ketoconazole, a potent CYP450 3A4 inhibitor, glasdegib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.4- and 2.4-fold, respectively, compared to administration of glasdegib alone. The interaction has not been studied with other, less potent CYP450 3A4 inhibitors. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

When administered with a high-fat, high-calorie meal (800 to 1000 total calories, 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories), glasdegib Cmax and AUC decreased by 31% and 16%, respectively.

MANAGEMENT: Glasdegib may be administered with or without food. Coadministration of grapefruit or grapefruit juice with glasdegib should preferably be avoided.

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.