Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of palbociclib, which is a substrate of the isoenzyme. In 12 healthy study subjects, administration of a single 125 mg dose of palbociclib with multiple 200 mg daily doses of itraconazole, a potent CYP450 3A4 inhibitor, resulted in 34% and 87% increases in palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to palbociclib administered alone. The risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis may be increased.

MANAGEMENT: Concomitant use of palbociclib with potent CYP450 3A4 inhibitors should generally be avoided. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. If no alternatives exist, consider reducing the palbociclib dosage to 75 mg once daily. Following discontinuation of the potent CYP450 3A4 inhibitor, the palbociclib dosage should be returned (after 3 to 5 half-lives of the inhibitor) to that used prior to initiation of the inhibitor.

ADJUST DOSING INTERVAL: According to the manufacturer, coadministration with a meal high in calories, fat, and protein reduces the absorption of indinavir. In ten patients given indinavir in this manner, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of indinavir decreased by an average of 84% and 77%, respectively. In contrast, grapefruit juice may have only minor effects on the oral bioavailability of indinavir. The manufacturer's package labeling states that administration of a single 400 mg dose of indinavir with 8 oz. of grapefruit juice decreased indinavir AUC by an average of 26%. Likewise, a study consisting of 14 HIV-infected subjects found no uniform nor significant changes in steady-state indinavir AUC during administration with double-strength grapefruit juice compared to water. There was, however, a delay in absorption (Tmax) due to grapefruit juice that is unlikely to be of clinical significance.

MANAGEMENT: To ensure maximal oral absorption, indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal (e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; corn flakes, skim milk and sugar).

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.