Midostaurin

Midostaurin Uses, Dosage, Side Effects, Food Interaction and all others data.

Midostaurin (as Rydapt) is a multitarget kinase inhibitor for the treatment for adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3. It was initially characterized as a potential broad-spectrum antineoplastic agent, with activity toward diverse solid and hematopoietic tumors . It was approved on April 28, 2017 and has shown to increase the overall survival rate in patients with AML as an adjunct therapy along with chemotherapeutic agents.

It targets multiple WT and mutated kinases that, when activated, constitutively stimulate aberrant signalling cascades that lead to malignancies such as AML and ASM. Alternative pharmacodynamic effect of midostaurin in prolonging QTc intervals was not clinically significant in patients with advanced SM or AML when compared to placebo. Midostaurin is therapeutically beneficial as a combination therapy for patients undergoing chemotherapy.

Trade Name Midostaurin
Availability Prescription only
Generic Midostaurin
Midostaurin Other Names 4'-N-benzoylstaurosporine, Midostaurin
Related Drugs Rydapt, Venclexta, omeprazole, Prilosec, lansoprazole, Prevacid, imatinib, Gleevec, vincristine, venetoclax
Weight 25mg
Type Oral capsule
Formula C35H30N4O4
Weight Average: 570.649
Monoisotopic: 570.226705462
Protein binding

Midostaurin predominantly binds to α1-acid glycoprotein in vitro. The parent drug and its metabolites are >99.8% bound to plasma proteins in vitro.

Groups Approved, Investigational
Therapeutic Class
Manufacturer
Available Country United States
Last Updated: September 19, 2023 at 7:00 am
Midostaurin
Midostaurin

Uses

Midostaurin is an antineoplastic agent used to treat high-risk acute myeloid leukemia (AML) with specific mutations, aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematologic neoplasm (SM-AHN), or mast cell leukemia (MCL).

Investigated for use/treatment in adult patients with high-risk acute myeloid leukemia (AML) who are FLT3 mutation-positive, agressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Midostaurin is also used to associated treatment for these conditions: Acute Myeloid Leukemia (AML), Malignant mast cell neoplasm, Systemic Mastocytosis, Systemic mastocytosis with associated hematological neoplasm

How Midostaurin works

It potently inhibits multiple receptor tyrosine kinases. Midostaurin and its major active metabolites CGP62221 and CGP52421 inhibit the activity of protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and WT and/or mutant FLT3 tyrosine kinases. Inhibition of FLT3 receptor signalling cascades induces apoptosis of target leukemia cells expressing target receptors and mast cells, in addition to its antiproliferative activity toward multiple cancer cell lines . Midostaurin also interacts with organic anion transporter (OATP) 1A1 and multidrug resistance protein (MRP)-2 according to preliminary in vitro studies.

Toxicity

In a fertility study involving female and male rats, there is evidence of reproductive toxicity including reduced sperm count and decline pregnancy rates when administering 0.01 to 0.1 times the recommended dose in humans. LD50 for oral midostaurin for mouse, rat and rabbit are 300mg/kg, 980mg/kg and 3200mg/kg, respectively . Incidences of pulmonary toxicities including interstitial lung disease and pneumonitis have occured in few patients undergoing midostaurin monotherapy or combination therapy.

Food Interaction

  • Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of midostaurin and may reduce its serum concentration.
  • Exercise caution with grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of midostaurin, which may increase its serum concentration.
  • Take with food. Taking midostaurin with food increases the AUC, but it also prolongs the Tmax and reduces Cmax.

[Major] GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of midostaurin.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Ketoconazole, a potent CYP450 3A4 inhibitor, has been shown to increase midostaurin systemic exposure (AUC) by greater than 10-fold in healthy volunteers.

Increased exposure to midostaurin may increase the risk of adverse effects such as nausea, vomiting, diarrhea, edema, hyperglycemia, hyperuricemia, QT prolongation, neutropenia, lymphopenia, thrombocytopenia, and anemia.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of midostaurin.

Relative to fasting conditions, midostaurin systemic exposure (AUC) increased by approximately 1.2-fold when administered with a standard meal (457 calories; 50 g fat, 21 g proteins, 18 g carbohydrates) and 1.6-fold when administered with a high-fat meal (1007 calories; 66 g fat, 32 g proteins, 64 g carbohydrates), while midostaurin peak plasma concentration (Cmax ) decreased by 20% and 27%, respectively.

MANAGEMENT: The manufacturer recommends taking midostaurin with food.

Midostaurin was administered with food in clinical trials.

Patients should avoid consumption of grapefruit and grapefruit juice during treatment with midostaurin.

Midostaurin Disease Interaction

Moderate: renal/liver dysfunction, lung toxicity

Volume of Distribution

The Vd of midostaurin is 95.2L. The parent drug and its main metabolites (CGP62221, CGP52421) are distributed in plasma in vitro.

Elimination Route

The time to reach maximum concentration ranges from 1-3 hrs in fasting patients. The maximum concentration and the time it takes to reach this concentration is reduced up to 20% in presence of a standard meal.

Half Life

Elimination half life is approximately 21 hrs for midostaurin, 32 hrs for CGP62221 and 482 hrs for CGP52421.

Clearance

The clearance values of during the initial formation of metabolites are 1.47 L/h for CGP62221 metabolite and 0.501 L/h for CGP52421. 28 days following the oral administration of midostaurin, the clearance of CGP52421 may increase up to 5.2 fold in a recommended dose of 25 mg, resulting in a 2.1- to 2.5-fold increase in total clearance of midostaurin .

Elimination Route

Accounting for 95% of recovered dose eliminated through fecal excretion, 91% was determined as metabolites and 4% as unchanged parent drug. Remaining 5% of the recovered dose is eliminated via renal excretion.

Innovators Monograph

You find simplified version here Midostaurin

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