Drug Interactions between ketoconazole and osimertinib

MONITOR CLOSELY: Coadministration with potent 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 significant. 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.

MONITOR CLOSELY: Osimertinib may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In two premarketing studies with 411 patients, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec. A pharmacokinetic/pharmacodynamic analysis performed in 210 patients from one of the studies suggested a concentration-dependent QTc interval prolongation of 14 msec at a dose of 80 mg daily. 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). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if osimertinib is used concomitantly with a potent CYP450 3A4 inhibitor that can prolong the QT interval. If coadministration is required, close monitoring for adverse effects such as diarrhea, QT prolongation, torsade de pointes arrhythmia, and cardiomyopathy is recommended. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting osimertinib therapy and periodically during treatment. Osimertinib should not be started if baseline QTc is greater than 500 msec. Likewise, treatment should be interrupted and adjusted in accordance with the product labeling in patients who develop QTc prolongation greater than 500 msec. 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. Permanently discontinue osimertinib in patients who develop QTc interval prolongation with life-threatening arrhythmia.