Drug Interactions between darunavir and infigratinib

ADJUST DOSING INTERVAL: Food may increase the oral bioavailability of infigratinib. Coadministration with a high-fat, high-calorie meal (800 to 1,000 calories, with approximately 50% of total calories from fat) in healthy subjects increased mean infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 60% to 80% and 80% to 120%, respectively, and increased the median time to Cmax from 4 hours to 6 hours. When coadministered with a low-fat, low-calorie meal (approximately 330 calories, with 20% of total calories from fat), mean infigratinib Cmax and AUC increased by 90% and 70%, respectively, while the median time to Cmax did not change.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of infigratinib and one of its active metabolites, BHS697, both of which are primarily metabolized by CYP450 3A4 in vitro. 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. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. Coadministration of infigratinib with multiple doses of itraconazole, a potent CYP450 3A4 inhibitor, increased infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 164% and 622%, respectively, and the AUC for the active metabolite, BHS697, by 174%. 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 infigratinib and BHS697 may increase the incidence and severity of serious adverse reactions such as infections, anemia, pyrexia, abdominal pain, hypercalcemia, hyperphosphatemia, ocular toxicity (e.g., retinal pigment epithelial detachment), sepsis, stomatitis, diarrhea, palmar-plantar erythrodysesthesia syndrome, increased blood creatinine, increased lipase, and onycholysis.

MANAGEMENT: Infigratinib should be administered on an empty stomach at least one hour before or two hours after food. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with infigratinib.

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ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.

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