Drug Interactions between mitotane and osimertinib

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations of osimertinib, which has been shown in vitro to be primarily metabolised by the isoenzyme. Reduced therapeutic efficacy of osimertinib should be anticipated. In a clinical pharmacokinetic study, the osimertinib systemic exposure (AUC) at steady state was reduced by 78% when given concomitantly with the potent CYP450 3A4 inducer rifampin (600 mg daily for 21 days). In addition, the AUC and peak plasma concentration (Cmax) of the pharmacologically active metabolite of osimertinib, AZ5104, also decreased by 82% and 78%, respectively. 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 osimertinib with potent CYP450 3A4 inducers should generally be avoided. However, if concomitant use is required, some authorities recommend increasing the dose of osimertinib to 160 mg daily during treatment with the potent 3A4 inducer and resumed at 80 mg daily, 3 weeks after discontinuation of the potent 3A4 inducer. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath.