Drug Interactions between midostaurin and Prevpac

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of midostaurin and its active metabolites, which are all substrates of the isoenzyme. The increase in midostaurin concentrations may be particularly pronounced when CYP450 3A4 inhibitors are administered during the first week of midostaurin administration. When a single 50 mg dose of midostaurin was administered to healthy volunteers on day 6 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 10 days), midostaurin systemic exposure (AUC) increased by 10.4-fold compared to administration with placebo. The AUC of the two active metabolites, CGP62221 and CGP52421, increased by 3.5- and 1.2-fold, respectively. When multiple doses of midostaurin (100 mg twice daily on days 1 and 2; 50 mg twice daily on days 3 to 28) were coadministered with itraconazole (100 mg twice daily on days 22 to 28 for 13 doses), the plasma concentrations on day 28 (Cmin) of midostaurin, CGP62221 and CGP52421 increased by 2.1-, 1.2- and 1.3-fold, respectively, compared to the corresponding day 21 Cmin concentrations with midostaurin alone.

MANAGEMENT: Concomitant use of midostaurin with potent CYP450 3A4 inhibitors should generally be avoided. If coadministration is required, patients should be closely monitored for increased adverse reactions (e.g., nausea, vomiting, diarrhea, edema, hyperglycemia, hyperuricemia, QT prolongation, neutropenia, lymphopenia, thrombocytopenia, anemia), especially during the first week of consecutive midostaurin administration in patients with advanced systemic mastocytosis and during the first week of midostaurin administration in each cycle of chemotherapy in patients with acute myeloid leukemia.

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.