Drug Interaction Report

Coadministration with moderate or potent inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations (AUC) of vibegron, which has been shown in vitro to be a substrate of the isoenzyme and transporter. Although CYP450 3A4 is the predominant enzyme in vibegron metabolism, metabolic pathways have only a minor role in the elimination of vibegron. In a phase 3 Japanese study, coadministration of vibegron (100 mg) with moderate (diltiazem) and potent (ketoconazole) inhibitors of CYP450 3A4, resulted in a 1.6- and 2.1-fold increase in vibegron AUC, respectively, which was not considered clinically significant. No dosage adjustment is recommended when vibegron is administered in combination with moderate or potent CYP450 3A4 and/or P-gp inhibitors.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.