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Melphalan flufenamide API Manufacturers & Suppliers

General Description:

Melphalan flufenamide, identified by CAS number 380449-51-4, is a notable compound with significant therapeutic applications. Melphalan flufenamide, also known as melflufen or J1, is a prodrug of . Melphalan flufenamide is more readily uptaken by cells than melphalan, and is cleaved to the active metabolite by aminopeptidases. _In vitro_ models show that melphalan is 10 to hundreds of times more potent than melphalan. The increased potency makes melphalan flufenamide a treatment option for patients with relapsed or refractory multiple myeloma who have attempted at least 4 lines of therapy already. Melphalan flufenamide was granted FDA approval on 26 February 2021. It has since been withdrawn from the market in the wake of the phase 3 OCEAN trial which showed a decrease in overall survival in comparison to standard treatment with and despite superior progression-free survival.

Indications:

This drug is primarily indicated for: Melphalan flufenamide is indicated in combination with to treat adults with relapsed or refractory multiple myeloma who have received ≥4 therapies and are refractory to at least one proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Melphalan flufenamide undergoes metabolic processing primarily in: Melphalan flufenamide is metabolised to desethyl-melphalan and melphalan. Melphalan is spontaneously hydrolyzed to monohydroxy-melphalan and dihydroxy-melphalan. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Melphalan flufenamide are crucial for its therapeutic efficacy: For a 40 mg intravenous infusion, the active metabolite reaches a C_max of 432 ng/mL, with a T_max of 4-15 minutes, and an AUC of 3143 h\*µg/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Melphalan flufenamide is an important consideration for its dosing schedule: The mean elimination half life of melphalan flufenamide is 2.1 minutes and of melphalan is 70 minutes. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Melphalan flufenamide exhibits a strong affinity for binding with plasma proteins: Data regarding the protein binding of melphalan flufenamide are not readily available. However, free melphalan is 60% bound to albumin, 20% bound to alpha-1-acid glycoprotein, and 10% bound to other proteins in plasma. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Melphalan flufenamide from the body primarily occurs through: Data regarding the route of elimination of melphalan flufenamide are not readily available. Free melphalan undergoes rapid and spontaneous decomposition, complicating studies on the route of elimination. However, it is expected to be mainly renally excreted. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Melphalan flufenamide is distributed throughout the body with a volume of distribution of: The mean volume of distribution of melphalan flufenamide is 35 L and of melphalan is 76 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Melphalan flufenamide is a critical factor in determining its safe and effective dosage: The mean clearance of melphalan flufenamide is 692 L/h and of melphalan is 23 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Melphalan flufenamide exerts its therapeutic effects through: Melphalan flufenamide is an alkylating agent indicated to treat relapsed or refractory multiple myeloma in Melphalan flufenamide has a long duration of action as it is given every 28 days. Patients should be counselled regarding risks of thrombocytopenia, neutropenia, anemia, infections, secondary malignancies, embryo-fetal toxicity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Melphalan flufenamide functions by: Melphalan flufenamide is a more lipophilic prodrug of melphalan, which allows it to be more readily uptaken by cells. It is likely taken up into malignant cells by passive diffusion, where it is hydrolyzed by aminopeptidase N. The expression of aminopeptidases, along with other hydrolytic enzymes, is upregulated in many malignant cells, making the hydrolysis reaction to melphalan more favourable in a malignant cell. Increased concentrations of free melphalan in malignant cells leads to rapid irreversible DNA damage and apoptosis, reducing the potential for the development of resistance. Free melphalan is an nitrogen mustard derivative alkylating agent. Melphalan attaches alkyl groups to the N-7 position of guanine and N-3 position of adenine, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error. It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Finally, melphalan can induce a number of different mutations. While melphalan induces phosphorylation of the DNA damage marker γ-H2AX in melphalan sensitive cells at 6 hours, melphalan flufenamide induces γ-H2AX at 2 hours. Melphalan flufenamide is also able to induce γ-H2AX in melphalan-resistant cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Melphalan flufenamide is categorized under the following therapeutic classes: Alkylating Activity, Alkylating Drugs, Amino Acids, Amino Acids, Aromatic, Amino Acids, Cyclic, Amino Acids, Peptides, and Proteins, Antineoplastic Agents, Antineoplastic Agents, Alkylating, Antineoplastic and Immunomodulating Agents, Hydrocarbons, Halogenated, Mustard Compounds, Narrow Therapeutic Index Drugs, Nitrogen Mustard Analogues, Nitrogen Mustard Compounds, Prodrugs. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Melphalan flufenamide include:

• logP: 4.04
• pKa: 7.13