Introduction
Rydapt (midostaurin) is an oral multi-targeted kinase inhibitor developed by Novartis Pharmaceuticals. It represents a significant advancement in the treatment of specific hematologic malignancies, particularly for patients with certain genetic mutations. Approved by the FDA in 2017, Rydapt is the first targeted therapy specifically indicated for FLT3-mutated acute myeloid leukemia (AML).
Mechanism of Action
Midostaurin inhibits multiple receptor tyrosine kinases through ATP-competitive binding. Its primary therapeutic action involves inhibition of FMS-like tyrosine kinase 3 (FLT3), which is constitutively activated by internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations in approximately 30% of AML patients. Additionally, Rydapt inhibits KIT (including the D816V mutation), platelet-derived growth factor receptors (PDGFRα/β), vascular endothelial growth factor receptor 2 (VEGFR2), and members of the serine/threonine kinase protein kinase C (PKC) family.
The drug induces apoptosis and inhibits proliferation of leukemic cells expressing FLT3-ITD and FLT3-TKD mutations. It also demonstrates activity against mast cells carrying the KIT D816V mutation, which is relevant for its use in advanced systemic mastocytosis.
Indications
Rydapt is FDA-approved for: 1. Newly diagnosed FLT3-mutant acute myeloid leukemia (AML): Used in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy in adult patients 2. Aggressive systemic mastocytosis (ASM): For adult patients with ASM, systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL)
The presence of FLT3 mutation must be confirmed by FDA-approved testing before initiating treatment for AML.
Dosage and Administration
Standard dosing: 50 mg orally twice daily with food AML-specific dosing:- Begin with each cycle of chemotherapy and continue until recovery from hematologic toxicity or until unacceptable toxicity
- Administer approximately 12 hours apart with food
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment (CrCl ≥30 mL/min). Use with caution in severe impairment.
- Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment (Child-Pugh A/B). Not studied in severe impairment.
- Elderly patients: No specific dosage adjustment required
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Median Tmax is 1-3 hours. High-fat meal increases AUC by 1.2-fold and Cmax by 1.6-fold. Distribution: Mean volume of distribution is 95 L. Protein binding is 99.8%, primarily to alpha-1 acid glycoprotein. Metabolism: Extensive hepatic metabolism primarily via CYP3A4, with contributions from CYP1A2, CYP2D6, and CYP2C8. Active metabolites include CGP62221 and CGP52421. Elimination: Primarily fecal excretion (95%), with renal elimination accounting for <5%. Terminal half-life is approximately 21 hours (midostaurin) and 32 hours (active metabolites).Contraindications
1. Hypersensitivity to midostaurin or any component of the formulation 2. Concurrent use with strong CYP3A4 inhibitors 3. Patients with congenital long QT syndrome
Warnings and Precautions
Pulmonary toxicity: Interstitial lung disease and pneumonitis, including fatal cases, have been reported. Monitor for pulmonary symptoms and discontinue if suspected. 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 last dose. QTc prolongation: May prolong QT interval. Monitor ECG and electrolytes at baseline and during treatment. Avoid in patients with congenital long QT syndrome. Photosensitivity: Photosensitivity reactions reported. Advise patients to use protective measures and avoid sun exposure. Lactation: Advise not to breastfeed during treatment and for at least 4 months after last dose.Drug Interactions
Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Contraindicated due to increased midostaurin exposure Strong CYP3A4 inducers (rifampin, carbamazepine): May decrease midostaurin efficacy CYP3A4 substrates: Midostaurin may increase exposure to sensitive CYP3A4 substrates QT-prolonging drugs: Additive effects possible; monitor ECGAdverse Effects
Most common (≥30%):- Febrile neutropenia
- Nausea
- Mucosal inflammation
- Vomiting
- Headache
- Petechiae
- Musculoskeletal pain
- Epistaxis
- Device-related infection
- Hyperglycemia
- Upper respiratory tract infection
- Pulmonary toxicity (10%)
- QT prolongation
- Photosensitivity
- Embryo-fetal toxicity
Monitoring Parameters
1. Complete blood counts with differential: Weekly during induction/consolidation, then as clinically indicated 2. Electrolytes (potassium, magnesium, calcium): Baseline and periodically 3. ECG: Baseline, during treatment, and as clinically indicated 4. Liver function tests: Baseline and periodically 5. Pulmonary function: Monitor for signs/symptoms of pneumonitis 6. FLT3 mutation status: Confirm before initiation in AML 7. Pregnancy testing: Before initiation in females of reproductive potential
Patient Education
1. Take exactly as prescribed with food approximately every 12 hours 2. Do not crush or open capsules 3. Report any signs of infection, unusual bleeding, or bruising immediately 4. Use effective contraception during treatment and for at least 4 months after discontinuation 5. Avoid sun exposure and use protective measures (sunscreen, protective clothing) 6. Report any breathing difficulties, cough, or chest pain 7. Inform all healthcare providers about Rydapt use due to potential drug interactions 8. Do not breastfeed during treatment 9. Report any dizziness, lightheadedness, or palpitations 10. Maintain all scheduled follow-up appointments and laboratory monitoring
References
1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-464. 2. Rydapt [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2022. 3. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016;374(26):2530-2541. 4. FDA Approval: Midostaurin for Newly Diagnosed FLT3-Mutated AML. FDA.gov. April 28, 2017. 5. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2023. 6. Levis MJ. Midostaurin approved for FLT3-mutated AML. Blood. 2017;129(26):3403-3406.