Drug Interactions between nirogacestat and osimertinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of osimertinib, which has been shown in vitro to be primarily metabolized by the isoenzyme. In a pharmacokinetic study of 36 patients with non-small cell lung cancer, coadministration with the potent CYP450 3A4 inhibitor itraconazole (200 mg twice daily) increased the area under the concentration-time curve (AUC) of osimertinib by 24% and decreased its peak plasma concentration (Cmax) by 20%. These pharmacokinetic changes are not expected to be clinically insignificant. However, a case report describes an 86-year-old woman on a stable dose of osimertinib (40 mg daily) who was started on itraconazole 200 mg daily and was observed to have an increase in osimertinib-associated adverse effects (grade 2 diarrhea) as well as elevated plasma trough concentrations of osimertinib that were approximately 1.7-fold greater than the mean concentration expected with an 80 mg daily dose. Upon a dosage reduction of osimertinib (40 mg every second day), the patient's diarrhea resolved, and its plasma trough concentrations returned to acceptable levels. The authors suggested that in addition to the itraconazole, the patient's age, her sarcopenia, as well as the mild to large interindividual variability in the pharmacokinetics of osimertinib may have contributed to the significance of the interaction. Clinical data for other less potent CYP450 3A4 inhibitors are not available. However, since osimertinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia).

MANAGEMENT: Caution is recommended if osimertinib is used concomitantly with a potent CYP450 3A4 inhibitor. If coadministration is required, close monitoring for adverse effects such as diarrhea, QT prolongation, torsade de pointes arrhythmia, and cardiomyopathy is recommended. Consultation with product labeling and local or institutional guidelines may be appropriate for further recommendations. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.