Drug Interactions between bosutinib and ivacaftor / lumacaftor

GENERALLY AVOID: Coadministration with potent and moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of bosutinib, which is primarily metabolised by the isoenzyme. In 24 healthy volunteers, administration of a single 500 mg dose of bosutinib with the potent CYP450 3A4 inducer rifampin (600 mg/day for 6 days) under fed conditions resulted in an 86% decrease in bosutinib peak plasma concentration (Cmax) and 94% decrease in systemic exposure (AUC) compared to administration of bosutinib alone. 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: Concomitant use of bosutinib with potent and moderate CYP450 3A4 inducers should be avoided due to the potential for reduced efficacy.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of bosutinib, which is a substrate of the isoenzyme and efflux transporter. In 24 healthy volunteers, administration of a single 100 mg dose of bosutinib with the potent CYP450 3A4 and P-gp inhibitor ketoconazole (400 mg/day for 5 days) under fasting conditions resulted in a 5.2-fold increase in bosutinib peak plasma concentration (Cmax) and 8.6-fold increase in systemic exposure (AUC) compared to administration of bosutinib alone. Ketoconazole also decreased the mean apparent clearance of bosutinib by approximately 9-fold and increased the mean terminal half-life from 46.2 hours to 69.0 hours. No data are available for use with less potent CYP450 3A4 inhibitors or P-gp inhibitors.

MANAGEMENT: Caution is advised when bosutinib is used with CYP450 3A4 or P-gp inhibitors. Patients should be monitored more closely for development of adverse effects such as diarrhea, nausea, vomiting, abdominal pain, myelosuppression, hepatotoxicity, and fluid retention (e.g., pericardial effusion, pleural effusion, pulmonary edema, peripheral edema).