Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of infigratinib and its two active metabolites, BHS697 and CQM157. Infigratinib and BHS697 are both primarily metabolized by CYP450 3A4 in vitro, while CQM157 is metabolized via both Phase I and Phase II biotransformation pathways. Coadministration of infigratinib with multiple doses of rifampin, a potent CYP450 and uridine diphosphate glucuronosyltransferase (UGT) inducer, decreased infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 44% and 56%, respectively. The active metabolites were similarly affected: the Cmax and AUC of BHS697 decreased by 27% and 65%, respectively, and those of CQM157 were decreased by 50% and 76%, respectively. Reduced efficacy of infigratinib may occur.

MANAGEMENT: Due to the potential for reduced pharmacologic effects, concomitant use of infigratinib with potent or moderate CYP450 3A4 inducers should be avoided.

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.