Drug Interactions between ivacaftor / lumacaftor and pazopanib

MONITOR: Coadministration with ivacaftor may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these pathways due to inhibition by ivacaftor and its pharmacologically active M1 metabolite. The interaction has been studied with midazolam and digoxin, probe substrates for CYP450 3A4 ad P-gp, respectively. In study subjects, midazolam systemic exposure (AUC) increased by 1.5-fold when it was administered with ivacaftor, suggesting weak inhibition of CYP450 3A4 by ivacaftor. Likewise, digoxin AUC increased by 1.3-fold with ivacaftor, which is also consistent with weak inhibition of P-gp by ivacaftor.

MANAGEMENT: Caution is advised when ivacaftor is used with drugs that are substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ivacaftor is added to or withdrawn from therapy.

GENERALLY AVOID: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of pazopanib, which is primarily metabolized by the isoenzyme. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: The use of pazopanib in combination with potent CYP450 3A4 inducers such as carbamazepine, dexamethasone, enzalutamide, phenobarbital, phenytoin, rifamycins, and St. John's wort should generally be avoided. Alternative treatment lacking CYP450 3A4-inducing activity should be considered in patients receiving pazopanib; otherwise, pazopanib should not be used. Other known CYP450 3A4 inducers include aminoglutethimide, barbiturates, bexarotene, bosentan, dabrafenib, efavirenz, nafcillin, nevirapine, somatrem, somatropin, and various other anticonvulsants, although the extent to which they may interact with pazopanib is unknown.