Drug Interaction Report

Coadministration with remdesivir may increase the plasma concentrations of drugs metabolized via CYP450 3A4, but many sources indicate that clinically significant interactions are unlikely. The proposed mechanism is inhibition of CYP450 3A4 by remdesivir. Two drug interaction studies were conducted using the sensitive CYP450 3A4 substrate, midazolam. In the first study, healthy volunteers (n=19) received a single dose of remdesivir (200 mg) and a single dose of midazolam (2.5 mg), which resulted in midazolam's maximum concentration (Cmax) and systemic exposure (AUC) increasing by 29% and 20%, respectively. In the second study, healthy volunteers (n=14) received remdesivir (200 mg once, followed by 100 mg daily) for a total of 10 doses and a single dose of midazolam (2.5 mg) administered with the last dose of remdesivir. Midazolam's Cmax and AUC increased by 45% and 30%, respectively. Both studies indicated that remdesivir is a weak in vivo inhibitor of CYP450 3A4; however, some authorities consider these findings to be clinically insignificant.

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.