Alkeran Mechanism of Action

Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, alkylating agents, nitrogen mustard analogues. ATC Code: L01AA03.
Pharmacology: Pharmacodynamics: Mechanism of Action: Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking two DNA strands and thereby preventing cell replication.
Pharmacokinetics: Absorption: Tab: The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma and peak plasma concentration.
In studies of the absolute bioavailability of melphalan, the mean absolute bioavailability ranged from 56 to 85%.
In a study of 18 patients administered melphalan 0.2 to 0.25 mg/kg body weight orally, a maximum plasma concentration (range 87 to 350 ng/mL) was reached within 0.5 to 2.0 hours.The administration of melphalan immediately after food delayed the time to achieving peak plasma concentrations and reduced the area under the plasma concentration-time curves by between 39 and 54%.
Inj: Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.
Distribution: Melphalan is moderately bound to plasma proteins with reported percent binding ranging from 69 to 78%. There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved in standard dose therapy, but that the binding may become concentration-dependent at the concentrations observed in high-dose therapy. Serum albumin is the major binding protein, accounting for about 55 to 60% the binding, and 20% is bound to α₁-acid glycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversible component attributable to the alkylation reaction with plasma proteins.
Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed in a single high-dose study in children.
Inj: Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m² body surface area (approximately 0.1 to 0.6 mg/kg body weight) to 10 patients with ovarian cancer or multiple myeloma, the mean volumes of distribution at steady state and central compartment were 29.1 ± 13.6 litres and 12.2 ± 6.5 litres, respectively.
In 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2- to 20-min infusion, the mean volumes of distribution at steady state and central compartment were, respectively, 40.2 ± 18.3 litres and 18.2 ± 11.7 litres.
Following hyperthermic (39°C) perfusion of the lower limb with melphalan at 1.75 mg/kg body weight in 11 patients with advanced malignant melanoma, mean volumes of distribution at steady state and central compartment were, respectively, 2.87 ± 0.8 litres and 1.01 ± 0.28 litres.
Biotransformation/Metabolism: In vivo and in vitro data suggest that spontaneous degradation rather than enzymatic metabolism is the major determinant of the drugs half-life in man.
Elimination: Tab: In 13 patients given oral melphalan at 0.6 mg/kg body weight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h.
In 18 patients administered melphalan 0.2 to 0.25 mg/kg body weight orally, the mean elimination half-life was 1.12 ± 0.15 h.
Inj: In 8 patients given a single bolus dose of 0.5 to 0.6 mg/kg body weight, the composite initial and terminal half-lives were reported to be 7.7 ± 3.3 minutes and 108 ± 20.8 minutes, respectively. Following injection of melphalan, monohydroxymelphalan and dihydroxymelphalan were detected in the patients' plasma, reaching peak levels at approximately 60 minutes and 105 minutes, respectively. A similar half-life of 126 ± 6 minutes was seen when melphalan was added to the patients' serum in vitro (37°C), suggesting that spontaneous degradation rather than enzymatic metabolism may be the major determinant of the drug's half-life in man.
Following administration of a 2-minute infusion of doses ranging from 5 to 23 mg/m² body surface area (approximately 0.1 to 0.6 mg/kg body weight) to 10 patients with ovarian cancer or multiple myeloma, the pooled initial and terminal half-lives were, respectively, 8.1 ± 6.6 minutes and 76.9 ± 40.7 minutes.
In 15 children and 11 adults given high-dose intravenous ALKERAN (140 mg/m² body surface area) with forced diuresis, the mean initial and terminal half-lives were found to be 6.5 ± 3.6 minutes and 41.4 ± 16.5 minutes, respectively (Ardiet et al., 1986). Mean initial and terminal half-lives of 8.8 ± 6.6 minutes and 73.1 ± 45.9 minutes, respectively, were recorded in 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2- to 20-minute infusion.
Following hyperthermic (39°C) perfusion of the lower limb with 1.75 mg/kg body weight, mean initial and terminal half-lives of 3.6 ± 1.5 minutes and 46.5 ± 17.2 minutes, respectively, were recorded in 11 patients with advanced malignant melanoma.
Special Patient Populations: Renal Impairment: Melphalan clearance may be decreased in renal impairment (see Renal Impairment under Dosage & Administration and Renal impairment under Precautions).
Elderly: No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Carcinogenesis, mutagenesis: Melphalan is mutagenic in animals.
Tab: Fertility studies: In mice, melphalan administered intraperitoneally at a dose of 7.5 mg/kg, showed reproductive effects attributable to cytotoxicity in specific male germ cell stages and induced dominant lethal mutations and heritable translocations in post-meiotic germ cells, particularly in mid to late stage spermatids.
A study was performed to measure the total reproductive capacity of melphalan in female mice. Females received a single intraperitoneal dose of 7.5 mg/kg melphalan and were then housed with an untreated male for most of their reproductive life span (a minimum of 347 days post-treatment). A pronounced reduction in litter size occurred within the first post-treatment interval, followed by an almost complete recovery. Thereafter, a gradual decline in litter size occurred. This was simultaneous with a reduction in the proportion of productive females, a finding associated with an induced reduction in the number of small follicles (see Use in Pregnancy & Lactation).