MIDOSTAURIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for MIDOSTAURIN (MIDOSTAURIN).
Midostaurin is a multikinase inhibitor that targets FLT3 (FMS-like tyrosine kinase 3), KIT, PDGFRα/β, VEGFR2, and PKC. It inhibits FLT3 receptor signaling and downstream MAPK/ERK and PI3K/AKT pathways, inducing apoptosis in FLT3-mutated cells.
| Metabolism | Primarily metabolized by CYP3A4, producing active metabolites CGP52421 (also CYP3A4) and CGP62221. Midostaurin is a substrate of CYP3A4 and also inhibits CYP3A4 and CYP2C9. |
| Excretion | Midostaurin is primarily eliminated via feces (approximately 95% of total radioactivity after a single 50 mg oral dose), with <5% excreted in urine. Biliary excretion is the major route for fecal elimination; unchanged midostaurin accounts for <10% of the dose, with the remainder as metabolites. |
| Half-life | The terminal elimination half-life (t½) of midostaurin is approximately 20 hours (range 17–22 h) for the parent drug and slightly longer for its active metabolite CGP52421 (~30 h). This supports twice-daily dosing while maintaining steady-state concentrations. |
| Protein binding | Midostaurin is approximately 99.8% bound to plasma proteins, primarily albumin and α-1-acid glycoprotein. This high binding influences volume of distribution and may be affected by hypoalbuminemia. |
| Volume of Distribution | The apparent volume of distribution (Vd/F) is approximately 1300 L (95 L/kg for a 70 kg patient), indicating extensive tissue distribution. This large Vd reflects penetration into tissues including bone marrow (target site for AML/mastocytosis). |
| Bioavailability | Absolute oral bioavailability of midostaurin is approximately 30% (range 20–40%). Food does not significantly alter bioavailability and the drug can be taken without regard to meals. |
| Onset of Action | For FLT3-mutated AML, clinical response (complete remission) is typically assessed within 1–2 months of continuous dosing. For systemic mastocytosis, symptomatic improvement may be observed within 2–4 weeks. Time to peak plasma concentration (Tmax) is 1.5–3 hours after oral administration, but therapeutic effect requires sustained exposure. |
| Duration of Action | Given the half-life, therapeutic plasma concentrations are maintained over the dosing interval (12 hours). Duration of action is continuous with twice-daily dosing; treatment is continued until disease progression or unacceptable toxicity. In AML, midostaurin is given in combination with chemotherapy for 14 days per cycle; response duration varies but median remission duration is approximately 4–5 months. |
| Molecular Weight | 570.63 |
50 mg orally twice daily with food for acute myeloid leukemia (AML) with FLT3 mutation; for advanced systemic mastocytosis, 100 mg orally twice daily.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild-to-moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), reduce dose to 50 mg twice daily and monitor for toxicity. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 50 mg twice daily. Child-Pugh C: avoid use. |
| Pediatric use | For pediatric AML with FLT3 mutation: 50 mg/m² orally twice daily (based on body surface area). Maximum dose 100 mg twice daily. |
| Geriatric use | No specific dose adjustment required; monitor renal function and consider reducing to 50 mg twice daily if eGFR <30 mL/min. Increased risk of QT prolongation. |
| 1st trimester | Avoid use due to potential teratogenicity based on animal studies and its mechanism of action (FLT3, KIT, and PKC inhibition). Women of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose. |
| 2nd trimester | Avoid use. May cause fetal harm based on animal studies and its mechanism of action. No adequate human data available. |
| 3rd trimester | Avoid use. Potential for fetal harm and risk of premature labor or low birth weight due to its antiangiogenic properties. Use only if benefit outweighs risk, with close monitoring. |
Clinical note
Comprehensive clinical and safety monograph for MIDOSTAURIN (MIDOSTAURIN).
| Placental transfer | Likely transferred across placenta based on molecular weight (<500 Da) and lipophilicity. In rats, radioactivity crossed placenta after oral administration. |
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential for serious adverse reactions in nursing infants (e.g., myelosuppression, gastrointestinal toxicity), advise women not to breastfeed during treatment and for at least 1 month after last dose. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to midostaurin or any excipientsPregnancy (unless benefit outweighs risk)BreastfeedingConcurrent use of strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort)
| Precautions | Pulmonary toxicity: Interstitial lung disease/pneumonitis, including fatalities. Monitor for pulmonary symptoms., Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose., Risk of hemorrhage: Severe bleeding events reported. Monitor platelet counts and manage bleeding promptly. |
| Food/Dietary | Take with food to reduce gastrointestinal upset. Avoid grapefruit, grapefruit juice, and Seville oranges as they inhibit CYP3A4 and can increase midostaurin levels, raising toxicity risk. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Midostaurin is embryotoxic and fetotoxic in animal studies. In first trimester, there is potential for major congenital malformations. In second and third trimesters, risk of growth restriction, fetal distress, and premature labor. Cases of spontaneous abortion documented. |
| Fetal Monitoring | Monthly complete blood count and cardiac function assessment (echocardiogram or MUGA) due to risk of QTc prolongation and myelosuppression. Serial growth ultrasounds and nonstress tests after viability for fetal monitoring. |
| Fertility Effects | May impair fertility in males and females; potentially irreversible azoospermia or ovarian failure. Advise cryopreservation before treatment if future fertility desired. |
| Clinical Pearls | Midostaurin is a multikinase inhibitor targeting FLT3, KIT, and other kinases. It is used in FLT3-mutated AML (induction/consolidation with chemotherapy) and advanced systemic mastocytosis. Significant QT prolongation risk; obtain baseline ECG and monitor electrolytes. CYP3A4 substrate; avoid strong CYP3A4 inhibitors and inducers. Administer with food to reduce nausea. Monitor for pulmonary toxicity (interstitial lung disease) and embryo-fetal harm. |
| Patient Advice | Take midostaurin exactly as prescribed, usually twice daily with food. · Do not open, crush, or chew the capsules; swallow whole. · Avoid grapefruit, grapefruit juice, and Seville oranges during treatment. · Report any signs of infection (fever, chills), irregular heartbeat, dizziness, or shortness of breath immediately. · Use effective contraception during treatment and for at least 4 months after the last dose. · Do not breastfeed while taking midostaurin. · Inform all healthcare providers you are taking midostaurin. · Store capsules at room temperature away from moisture and heat. |