From the Guidelines
The NCCN clinical practice guidelines in oncology study advocated for consideration of alternative concomitant therapies that do not strongly inhibit CYP3A activity, rather than a specific dose reduction of midostaurin to 25 mg per day in patients receiving strong CYP3A4 inhibitors. However, it is crucial to note that co-administration of midostaurin with strong CYP3A inhibitors may increase midostaurin concentrations, potentially leading to toxicity 1. Normally, midostaurin is dosed at 100 mg twice daily, but when used with CYP3A4 inhibitors, a dose reduction may be necessary to avoid toxicity. Midostaurin is extensively metabolized by CYP3A4 in the liver, and inhibition of this enzyme pathway leads to decreased clearance and potentially dangerous accumulation of the drug. Patients should be monitored closely for increased side effects such as nausea, vomiting, and QT prolongation even with the reduced dose.
- Key points to consider:
- Midostaurin starting dose is 100 mg twice daily with food
- Co-administration with strong CYP3A inhibitors may increase midostaurin concentrations
- Consider alternative concomitant therapies that do not strongly inhibit CYP3A activity, as suggested by the study 1
- Close monitoring of patients for increased side effects is necessary when midostaurin is used with CYP3A4 inhibitors.
From the Research
Midostaurin Dose Reduction
- The study that advocated for the reduction of midostaurin dose to 25 mg per day in patients receiving strong CYP3A4 inhibitors is not explicitly stated in the provided evidence.
- However, the study 2 investigated the effect of CYP3A4 inhibitors on midostaurin pharmacokinetics and found that inhibition of CYP3A4 by ketoconazole increased midostaurin exposure more than tenfold.
- Another study 3 developed a pharmacokinetic model to predict the effect of CYP3A4 inhibitors on midostaurin exposure and found that the model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole.
- The study 4 evaluated the pharmacokinetics of midostaurin in patients with diabetes mellitus and found that the plasma exposures of midostaurin and its metabolites increased less than proportionally over the dose range of 25 to 100 mg.
- The study 5 conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in patients with advanced systemic mastocytosis and found that dose reduction owing to toxic effects occurred in 56% of the patients, but it does not specifically mention reducing the dose to 25 mg per day in patients receiving strong CYP3A4 inhibitors.
- It is worth noting that none of the provided studies explicitly recommend reducing the midostaurin dose to 25 mg per day in patients receiving strong CYP3A4 inhibitors, but they do highlight the importance of considering drug-drug interactions when administering midostaurin with CYP3A4 inhibitors 6, 2, 3.