Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate to potent inducers of CYP450 3A4 may significantly reduce the plasma levels and effects of lazertinib, which is primarily metabolized by the isoenzyme. In a phase 1 study of healthy adult participants, concomitant use of the strong CYP450 3A4 inducer rifampin reduced the peak plasma concentration (Cmax) and systemic exposure (AUC) of lazertinib by 72% and 83%, respectively. Likewise, a pharmacokinetic model predicted that concomitant use with the moderate CYP450 3A4 inducer efavirenz would decrease lazertinib's steady state Cmax and AUC by at least 32% and 44%, respectively.

MANAGEMENT: The manufacturer recommends avoiding concomitant use with a strong or moderate CYP450 3A4 inducer due to a potential reduction in the efficacy of lazertinib. Consider use of an alternative concomitant medication with no potential to induce CYP450 3A4.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. The interaction occurs to a greater extent when ivacaftor is administered as monotherapy than when administered in combination with lumacaftor, a potent CYP450 3A4 inducer. In study subjects, ivacaftor systemic exposure (AUC) increased by 8.5-fold when it was administered concomitantly with the potent CYP450 3A4 inhibitor ketoconazole and by 3-fold with the moderate CYP450 3A4 inhibitor fluconazole. By contrast, when lumacaftor/ivacaftor was coadministered with the potent CYP450 3A4 inhibitor itraconazole, ivacaftor peak plasma concentration (Cmax) and AUC increased by an average of 3.7- and 4.3-fold, respectively, and when coadministered with the moderate CYP450 3A4 inhibitor ciprofloxacin, ivacaftor Cmax and AUC increased by just 29% each.

MANAGEMENT: Caution is advised if ivacaftor is used with CYP450 3A4 inhibitors. A dosage adjustment for ivacaftor may be required if undue adverse effects occur.

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.