Melphalan, an alkylating agent used in the treatment of various cancers such as multiple myeloma and ovarian carcinoma, was developed in the 1950s as part of early research into nitrogen mustard derivatives for anticancer therapy. It was introduced into clinical use in the 1960s and became an important chemotherapeutic agent due to its effectiveness in targeting rapidly dividing cells. Melphalan works by cross-linking DNA strands, thereby inhibiting DNA replication and transcription, leading to cell death. It is widely used in oncology, particularly in high-dose regimens for bone marrow transplantation and in combination therapies for hematological malignancies. Over time, its role has expanded in cancer treatment protocols, supported by clinical studies demonstrating its efficacy, especially in multiple myeloma.
BRAND NAMES
Alkeran (most widely known brand)
Evomela (used especially for intravenous formulations)
MECHANISM OF ACTION
Melphalan is a bifunctional alkylating agent of the nitrogen mustard class that exerts its cytotoxic effect by forming covalent bonds with DNA. It primarily alkylates the N7 position of guanine bases, leading to the formation of intra- and interstrand DNA cross-links.
PHARMACOKINETICS
Absorption
Melphalan is variably absorbed after oral administration, with bioavailability ranging from approximately 25–50% due to instability in the gastrointestinal tract and first-pass metabolism. Peak plasma concentrations are typically reached within 0.5 to 2 hours after oral dosing.
Distribution
Melphalan has a relatively moderate volume of distribution, typically reported in the range of 0.5–1.0 L/kg, indicating distribution beyond the plasma into body tissues. It shows moderate plasma protein binding (approximately 60–90%), mainly to albumin.
Metabolism
Melphalan undergoes minimal hepatic metabolism compared to many other alkylating agents. A portion of the drug is spontaneously degraded in plasma and tissues through hydrolysis to inactive metabolites.
Elimination
Melphalan is eliminated primarily through renal excretion, with a significant proportion of the drug and its metabolites excreted in the urine. A smaller fraction may be eliminated via non-renal pathways, including spontaneous degradation in plasma and tissues.
PHARMACODYNAMICS
Melphalan is a bifunctional alkylating agent that exerts its cytotoxic effects by forming reactive ethyleneimmonium intermediates that alkylate DNA, primarily at the N7 position of guanine. This leads to the formation of interstrand and intrastrand DNA cross-links, which disrupt DNA replication and transcription. The resulting DNA damage prevents normal cell division and triggers apoptosis, particularly in rapidly dividing malignant cells.
ADMINISTRATION
Melphalan is administered either orally in tablet form or intravenously as an injection or infusion. Oral melphalan should be taken on an empty stomach to improve absorption, and the tablets are usually swallowed whole with water without breaking or chewing. Intravenous administration is used in high-dose chemotherapy regimens, particularly in conditioning protocols before stem cell transplantation, and allows precise dosing under medical supervision.
DOSAGE AND STRENGTH
Melphalan is available in 2 mg oral tablets and as intravenous formulations (lyophilized powder, commonly 50 mg vials). The dosage varies widely depending on the indication and treatment protocol. For multiple myeloma, the usual oral dose is 0.15 mg/kg/day for 4 days, repeated every 4–6 weeks, often in combination with other agents.
DRUG INTERACTIONS
Melphalan may interact with other myelosuppressive agents such as cyclophosphamide, busulfan, or other cytotoxic drugs, leading to additive bone marrow suppression (e.g., increased risk of leukopenia, thrombocytopenia, and anemia). Concomitant use with radiation therapy can also enhance hematologic toxicity.
FOOD INTERACTIONS
Food significantly affects the absorption of oral melphalan. When taken with food, especially high-fat meals, the absorption of melphalan is reduced and delayed, leading to lower and more variable plasma concentrations.
CONTRAINDICATIONS
Melphalan is contraindicated in patients with known hypersensitivity to melphalan or other alkylating agents. It should not be used in individuals with severe bone marrow suppression unless the potential benefit outweighs the risk, due to its strong myelosuppressive effects. Use is generally avoided during pregnancy, as it is teratogenic and can cause fetal harm.
SIDE EFFECTS
Bone marrow suppression (most common; leads to anemia, leukopenia, thrombocytopenia)
Increased risk of infections due to immunosuppression
Nausea and vomiting
Diarrhea
Mouth ulcers (stomatitis)
Loss of appetite (anorexia)
Hair loss (alopecia)
OVER DOSE
Melphalan overdose can lead to severe and potentially life-threatening toxicity, primarily due to profound bone marrow suppression. Symptoms may include severe leukopenia, thrombocytopenia, anemia, increased susceptibility to infections, bleeding tendencies, and mucositis.
TOXICITY
Melphalan toxicity is primarily dose-related and most significantly affects the bone marrow, leading to severe myelosuppression manifested as leukopenia, thrombocytopenia, and anemia. This increases the risk of life-threatening infections, bleeding, and fatigue.
