Drug Interactions between duvelisib and ivacaftor / tezacaftor

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.

ADJUST DOSE: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of vanzacaftor, tezacaftor and deutivacaftor, which are primarily metabolized by the isoenzyme. In clinical studies, itraconazole, a potent CYP450 3A4 inhibitor increased vanzacaftor systemic exposure (AUC) by 6.4-fold, tezacaftor AUC by 4 to 4.5-fold and deutivacaftor AUC by 11.1-fold. Erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor peak plasma concentration (Cmax) and AUC by 3.2- and 3.3-fold, respectively, and deutivacaftor Cmax and AUC by 2.9- and 4.1-fold, respectively. Likewise, fluconazole, another moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor and deutivacaftor Cmax and AUC by 2.6- and 2.5-fold; and 3.1- and 2.3-fold, respectively. The risk and/or severity of serious side effects such as liver damage may be increased.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For vanzacaftor/tezacaftor/deutivacaftor:
- For patients 6 to less than 12 years old, weighing less than 40 kg:
Potent CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100mg).
Moderate CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg).

- For patients 6 years old to less than 12 years old, weighing 40 kg or more:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week.
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

-For patients 12 years old and older:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

For tezacaftor/ivacaftor:
- The morning dose of tezacaftor/ivacaftor should be reduced to one tablet twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. 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 morning dose of 2 elexacaftor/tezacaftor/ivacaftor tablets once a day should be reduced to 2 tablets twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. 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.