4'-N-benzoylstaurosporine

Uses

4'-N-benzoylstaurosporine 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).

4'-N-benzoylstaurosporine 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 4'-N-benzoylstaurosporine works

It potently inhibits multiple receptor tyrosine kinases. 4'-N-benzoylstaurosporine 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 . 4'-N-benzoylstaurosporine 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.

4'-N-benzoylstaurosporine was administered with food in clinical trials.

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

4'-N-benzoylstaurosporine Drug Interaction

Moderate: prochlorperazine, diltiazem, apixaban, sacubitril / valsartan, dapagliflozin, glycerinMinor: sulfamethoxazole / trimethoprimUnknown: charcoal, thyroid desiccated, ubiquinone, copper gluconate, glucose, multivitamin, ginger, eplerenone, sodium iodide, arginine, metoprolol, metoprolol, pyridoxine

4'-N-benzoylstaurosporine 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

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