Drug Interaction Report

ADJUST DOSE: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of atogepant, which is primarily metabolized by the isoenzyme. When atogepant was administered in healthy study subjects with steady-state rifampin, a potent CYP450 3A4 inducer, atogepant peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 30% and 60%, respectively. No dedicated drug interaction studies were conducted to assess concomitant use with moderate CYP450 3A4 inducers, but reduced atogepant exposure would be expected.

MANAGEMENT: The recommended dosage of atogepant is 30 mg or 60 mg once daily when used concomitantly with potent or moderate CYP450 3A4 inducers.

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of atogepant, which is primarily metabolized by the isoenzyme. When atogepant was administered with the potent CYP450 3A4 inhibitor itraconazole in healthy study subjects, atogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 2.2- and 5.5-fold, respectively. However, moderate and weak inhibitors may interact to a much lesser extent. Population pharmacokinetic modeling has suggested that moderate (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak (e.g., cimetidine, esomeprazole) CYP450 3A4 inhibitors may increase atogepant AUC by 1.7- and 1.1-fold, respectively. The changes in atogepant exposure when coadministered with moderate or weak CYP450 3A4 inhibitors are not expected to be clinically significant.

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.