Drug Interactions between crizotinib and ivacaftor / lumacaftor

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. In study subjects, ivacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 2.5- and 3.0-fold when it was administered concomitantly with fluconazole, a moderate CYP450 3A4 inhibitor. When lumacaftor/ivacaftor was coadministered with ciprofloxacin, another moderate CYP450 3A4 inhibitor, lumacaftor Cmax and AUC decreased by 12% and 14%, respectively, while ivacaftor Cmax and AUC increased by 29% each. These changes are not considered clinically significant. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with moderate CYP450 3A4 inhibitors may increase elexacaftor AUC by 1.9- to 2.3-fold and tezacaftor AUC by approximately 2.1-fold.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For ivacaftor - For patients aged 6 months and older the frequency of dosing should be reduced to 1 tablet or packet once a day when coadministered with moderate CYP450 3A4 inhibitors. Patients should continue to receive the same tablet or oral granule packet strength, but instead of dosing twice a day, the frequency should be reduced to once a day. For example, ivacaftor 150 mg twice a day should be 150 mg once a day, ivacaftor 50 mg twice a day should be 50 mg once a day, etc. Use of ivacaftor with moderate or strong CYP450 3A4 inhibitors is not recommended in patients less than 6 months of age.
For lumacaftor/ivacaftor - No dosage adjustment is necessary when coadministered with moderate CYP450 3A4 inhibitors.
For tezacaftor/ivacaftor - The frequency of dosing should be reduced to a single morning dose of one tezacaftor/ivacaftor tablet alternating with one ivacaftor tablet every other morning during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.
For elexacaftor/tezacaftor/ivacaftor - The frequency of dosing should be reduced to a single morning dose of two elexacaftor /tezacaftor /ivacaftor tablets alternating with one ivacaftor tablet every other day during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

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GENERALLY AVOID: Coadministration with strong CYP450 3A4 inducers may decrease plasma concentrations and pharmacologic effects of crizotinib, which is primarily metabolized by the isoenzyme. In study subjects, administration of a single 250 mg oral dose of crizotinib during treatment with the strong CYP450 3A4 inducer rifampin (600 mg once daily) resulted in an approximately 69% decrease in crizotinib peak plasma concentration (Cmax) and an 82% decrease in systemic exposure (AUC) compared to crizotinib administered alone. Crizotinib steady state Cmax and AUCinf decreased by 79% and 84%, respectively, following repeated coadministration of crizotinib (250 mg twice daily) and rifampin (600 mg once daily) compared to crizotinib alone.

MANAGEMENT: Concomitant use of crizotinib with strong CYP450 3A4 inducers such as rifampin, carbamazepine, phenobarbital, and phenytoin should generally be avoided. Some authorities also advise against concomitant use with moderate CYP450 3A4 inducers.

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