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Melphalan | CAS No: 148-82-3 | GMP-certified suppliers
A medication that provides high-dose conditioning prior to stem cell transplantation and palliative treatment for multiple myeloma, ovarian carcinoma, and uveal melanoma with hepatic metastases.
Therapeutic categories
Primary indications
- Melphalan is indicated for use as a high-dose conditioning treatment prior to hematopoietic stem cell transplantation in patients with multiple myeloma
- It is also indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary
- Melphalan is a component of HEPZATO KIT, a liver-directed therapy indicated for the treatment of adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation
Product Snapshot
- Melphalan is available in oral and parenteral formulations, including injection powder for solution and film-coated tablets
- It is primarily indicated for high-dose conditioning prior to hematopoietic stem cell transplantation in multiple myeloma, palliative treatment of multiple myeloma, and palliative care of non-resectable ovarian epithelial carcinoma, as well as part of liver-directed therapy for uveal melanoma with unresectable hepatic metastases
- Melphalan holds regulatory approvals in key markets including the United States, Canada, and the European Union
Clinical Overview
Clinically, melphalan is indicated as a high-dose conditioning agent prior to hematopoietic stem cell transplantation in multiple myeloma patients. It is also employed in palliative treatment for multiple myeloma and non-resectable epithelial ovarian carcinoma. Additionally, melphalan forms the key cytotoxic component of the HEPZATO KIT, a liver-directed therapy approved for adults with uveal melanoma exhibiting hepatic metastases confined largely to the liver and limited or no extrahepatic disease.
Pharmacodynamically, melphalan exhibits cytotoxic, immunosuppressive, and myeloablative effects. It induces chromosomal aberrations and DNA interstrand cross-links leading to inhibition of DNA synthesis and transcription. This mechanism disrupts tumor cell replication and induces apoptosis in both resting and proliferating cells. The drug is taken up by tumor cells through a neutral amino acid transport pathway that it shares with leucine. Melphalan’s cytotoxicity contributes to dose-limiting bone marrow suppression and carries potential leukemogenic risk.
Pharmacokinetic data indicate that melphalan’s distribution targets rapidly dividing tissues, with metabolism and elimination processes influencing its narrow therapeutic index. Safety considerations include myelosuppression, potential cardiac effects such as transient heart rate increases during high-dose regimens, and a risk profile consistent with alkylating agents, demanding careful dose adjustments and monitoring.
Melphalan is classified within multiple drug categories including alkylating drugs, antineoplastic agents, immunosuppressants, and nitrogen mustard analogues. Regulatory-approved formulations require adherence to strict quality and purity standards to ensure consistent potency, especially given the narrow therapeutic window and known toxicities. API procurement must prioritize suppliers capable of providing material compliant with pharmacopeial specifications and manufactured under GMP conditions to support clinical and commercial drug product manufacturing.
Identification & chemistry
| Generic name | Melphalan |
|---|---|
| Molecule type | Small molecule |
| CAS | 148-82-3 |
| UNII | Q41OR9510P |
| DrugBank ID | DB01042 |
Pharmacology
| Summary | Melphalan is a bischloroethylamine alkylating agent that exerts cytotoxic effects by forming inter-strand DNA cross-links primarily at the N7 position of guanine, disrupting DNA synthesis and transcription. It is actively taken up by tumor cells via a neutral amino acid transport pathway and exhibits cytotoxic, immunosuppressive, and myeloablative activities. Melphalan’s pharmacodynamic profile includes DNA and protein cross-linking leading to chromosomal aberrations and bone marrow suppression. |
|---|---|
| Mechanism of action | Melphalan is an alkylating agent of the bischloroethylamine type. It is believed to be taken up by tumour cells via a neutral amino acid active pathway shared by leucine. Melphalan binds at the N7 position of guanine and induces inter-strand cross-links in DNA, disrupting DNA synthesis or transcription. It can also cause DNA-protein cross-linking and induce lesions in RNA, proteins, and lipids.[A1635, A230158, A230163, A261155, A261171, L47890] Melphalan is cytotoxic in resting and rapidly dividing tumour cells. |
| Pharmacodynamics | Melphalan possesses cytotoxic, immunosuppressive, and myeloablative activities.[A261150, L40928] Melphalan produces chromosomal aberrations _in vitro_ and _in vivo_; thus, it is considered to be potentially leukemogenic in humans. It also causes dose-limiting bone marrow suppression. The peak mean heart rate increased by 20 bpm from baseline following melphalan 100 mg/m<sup>2</sup> for two consecutive days in multiple myeloma patients undergoing autologous stem cell transplantation. |
Targets
| Target | Organism | Actions |
|---|---|---|
| DNA | Humans | cross-linking/alkylation |
ADME / PK
| Absorption | The absorption of oral melphalan is highly variable concerning both the time to the first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (C<sub>max</sub>). The average absolute bioavailability of melphalan ranges from 56% to 93%. High variability in bioavailability may be due to incomplete intestinal absorption, variable first-pass hepatic metabolism, or rapid hydrolysis. T<sub>max</sub> was one hour in patients who received single oral doses of 0.2 mg/kg to 0.25 mg/kg of melphalan. Oral administration of melphalan with a high-fat meal may reduce melphalan exposure (AUC) by 36% to 54%. Mean (± SD) C<sub>max</sub> and AUC<sub>0-inf</sub> were 5.8 ± 1.5 mcg/mL and 451 ± 109 mcg x min/mL, respectively, following intravenous administration of 100 mg/m<sup>2</sup> in multiple myeloma patients. |
|---|---|
| Half-life | In patients given a single oral dose of 0.6 mg/kg of melphalan, the terminal elimination plasma half-life (± SD) was 1.5 ± 0.83 hours. Following intravenous administration, the terminal elimination half-life is approximately 75 minutes. |
| Protein binding | Protein binding of melphalan ranges from 50% to 90%. Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1-acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is covalently and irreversibly bound to plasma proteins.[L40928, L47890] |
| Metabolism | Melphalan primarily undergoes chemical hydrolysis to inactive metabolites, monohydroxymelphalan and dihydroxymelphalan.[L40928, L47890] No other melphalan metabolites have been observed in humans. |
| Route of elimination | About 5.8% to 21.3% of melphalan is excreted in urine. |
| Volume of distribution | The volume of distribution of melphalan ranges from approximately 35.5 to 185.7 L/m<sup>2</sup>. Penetration into cerebrospinal fluid is low. |
| Clearance | Average total body clearance (CL) ranges from approximately 250 to 325 mL/min/m<sup>2</sup>. |
Formulation & handling
- Melphalan is available in both oral and injectable formulations, including intravenous and intra-arterial routes, indicating flexibility in administration.
- As a small molecule phenylalanine derivative, Melphalan does not possess peptide or biologic characteristics, which simplifies handling and stability considerations.
- Lyophilized powder forms require careful reconstitution under aseptic conditions and appropriate storage to maintain chemical stability prior to use.
Regulatory status
| Lifecycle | The API is marketed in the US, Canada, and EU with patent protection in Canada expired in 2017, while US patents extend through 2034, indicating ongoing market exclusivity primarily in the US and potential for generic competition in Canada. |
|---|
| Markets | US, Canada, EU |
|---|
Supply Chain
| Supply chain summary | Melphalan is manufactured and packaged by multiple companies, including both originator and contract manufacturing organizations, indicating a diversified supply base. Its branded products, primarily marketed under the name Alkeran, have a presence in the US, Canada, and EU markets. Although some patents have recently expired, active patents in the US extending to 2029 and beyond suggest limited immediate generic competition in certain regions. |
|---|
Safety
| Toxicity | The oral and intraperitoneal LD<sub>50</sub> in rats is 4484 µg/kg and 11200 µg/kg, respectively. The subcutaneous LD<sub>50</sub> in mice is 32 mg/kg. Overdoses resulting in death have been reported with melphalan. Overdoses, including intravenous doses up to 290 mg/m<sup>2</sup> and oral doses up to 50 mg/day for 16 days, have been reported. Symptoms of overdose include severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, cholinomimetic effects, mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract. Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia, caused by an associated inappropriate secretion of ADH syndrome, has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone marrow suppression. Melphalan is not removed from plasma via hemodialysis, and overdose is typically managed by general supportive measures, with appropriate blood transfusions and antibiotics.[L40928, L47890] |
|---|
- Melphalan exhibits acute toxicity with variable LD50 values depending on administration route, including 4
- 484 mg/kg orally and 32 mg/kg subcutaneously in rodent models
- Overdose may cause severe systemic toxicities such as bone marrow suppression, gastrointestinal hemorrhage, neurotoxicity, and hepatic veno-occlusive disease
Melphalan is a type of Alkylating agents
Alkylating agents are a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a significant role in cancer treatment. These compounds possess the ability to attach alkyl groups to the DNA molecule, effectively disrupting its structure and preventing cell replication. This mechanism of action makes alkylating agents potent chemotherapy drugs for various types of cancers.
Alkylating agents are often classified based on their chemical structure, which includes nitrogen mustards, ethylenimines, nitrosoureas, and alkyl sulfonates, among others. Each subclass exhibits unique chemical properties and therapeutic applications. For instance, nitrogen mustards like cyclophosphamide and mechlorethamine are used to treat lymphomas and leukemia, while nitrosoureas such as carmustine and lomustine are effective against brain tumors.
The alkylating agents' mode of action involves the transfer of alkyl groups to cellular components, primarily DNA. This leads to the formation of DNA adducts, cross-links, and DNA strand breaks, ultimately hindering DNA replication and causing cell death. The indiscriminate nature of alkylating agents can also affect healthy cells, leading to various side effects such as bone marrow suppression and gastrointestinal disturbances.
Despite their potential side effects, alkylating agents remain valuable tools in cancer therapy due to their broad spectrum of activity against different types of tumors. Ongoing research focuses on developing more selective and targeted alkylating agents to improve their therapeutic index and minimize adverse effects. The use of alkylating agents in combination with other chemotherapy drugs or radiation therapy is also being explored to enhance treatment outcomes and reduce drug resistance.
In conclusion, alkylating agents are an essential subclass of pharmaceutical APIs widely employed in cancer treatment. Their ability to disrupt DNA structure and impede cell replication makes them effective against various types of tumors, although careful management of side effects is necessary. Ongoing advancements and research continue to refine their therapeutic potential in the fight against cancer.
Melphalan (Alkylating agents), classified under Anticancer drugs
Anticancer drugs belong to the pharmaceutical API (Active Pharmaceutical Ingredient) category designed specifically to combat cancer cells. These powerful medications play a crucial role in cancer treatment and are developed to target and destroy cancerous cells, preventing their growth and spread.
Anticancer drugs are classified based on their mode of action and can include various types such as chemotherapy drugs, targeted therapy drugs, immunotherapy drugs, and hormonal therapy drugs. Chemotherapy drugs work by interfering with the cell division process, thereby inhibiting the growth of cancer cells. Targeted therapy drugs, on the other hand, are designed to attack specific molecules or genes involved in cancer growth, minimizing damage to healthy cells. Immunotherapy drugs stimulate the body's immune system to recognize and destroy cancer cells. Hormonal therapy drugs are used in cancers that are hormone-dependent, such as breast or prostate cancer, to block the hormones that fuel cancer cell growth.
These APIs are typically synthesized through complex chemical processes in state-of-the-art manufacturing facilities. Stringent quality control measures ensure the purity, potency, and safety of these drugs. Anticancer APIs undergo rigorous testing and adhere to stringent regulatory guidelines before being approved for clinical use.
Due to their critical role in cancer treatment, anticancer drugs are in high demand worldwide. Researchers and pharmaceutical companies continually strive to develop new and more effective APIs in this category to enhance treatment outcomes and minimize side effects. The ongoing advancements in the field of anticancer drug development offer hope for improved cancer therapies and better patient outcomes.
Melphalan API manufacturers & distributors
Compare qualified Melphalan API suppliers worldwide. We currently have 13 companies offering Melphalan API, with manufacturing taking place in 6 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Biophore India | Producer | India | India | CEP, CoA, GMP, USDMF | 46 products |
| ChemCon GmbH | Producer | Germany | Germany | CoA, GMP, MSDS | 36 products |
| ChemPacific | Producer | United States | Unknown | CoA, USDMF, WC | 10 products |
| Dalian Wista Pharma Co Lt... | Producer | China | China | CoA | 16 products |
| Emcure Pharma | Producer | India | India | CoA, USDMF | 80 products |
| Farmabios | Producer | Italy | Italy | CoA, ISO9001, USDMF | 58 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
| Hetero Labs | Producer | India | India | CoA, GMP, USDMF, WC | 90 products |
| Kromozome | Distributor | India | India | CoA, GMP | 17 products |
| NAVINTA | Producer | United States | Unknown | CoA, USDMF | 15 products |
| Shilpa Medicare Ltd | Producer | India | India | BSE/TSE, CoA, EDMF/ASMF, GMP, ISO9001, MSDS, USDMF, WC | 54 products |
| Sionc Pharma | Producer | India | India | CoA, WC | 10 products |
| Veeprho Group | Producer | Czech Republic | Czech Republic | CoA | 133 products |
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