Drug Interactions between osimertinib and Prevpac

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.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.