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 anti-neoplastic agent with some immunosuppressant properties. 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: 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%. Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.
In a study of 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, a maximum plasma concentration (range 87 to 350 nanograms/ml) was reached within 0.5 to 2.0 h.
The administration of melphalan tablets 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%.
Distribution: 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 paediatrics.
Elimination: In 13 patients given oral melphalan at 0.6 mg/kg bodyweight, 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 bodyweight orally, the mean elimination half‑life was 1.12±0.15 h.
Special Patient Populations: Renal impairment: Melphalan clearance may be decreased in renal impairment (see Dosage & Administration and 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: Mutagenicity: Melphalan is mutagenic in animals.
Reproductive toxicity: Reproduction studies in rats treated with oral doses of 0.81-2.42 times the Maximum Recommended Human Dose (MRHD) revealed embryolethal and teratogenic effects. Congenital anomalies included those of the brain (underdevelopment, deformation, meningocele, and encephalocele), eye (anophthalmia and micropthalmos), reduction of the mandible and tail, and hepatocele (see Use in Pregnancy & Lactation).
Fertility Studies: In mice, melphalan at clinically relevant exposure levels 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.
Females received melphalan at clinically relevant exposure levels and were then housed with an untreated male for most of their reproductive life span. 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).
Genotoxicity: Melphalan has been tested for genotoxicity in a number of short-term assays, both in vitro and in vivo.
In mice, oral administration of melphalan at a dose of 0.81 times the MRHD increased frequencies of dominant lethal mutations, chromosomal aberrations, sister chromatic exchange, micronuclei and DNA strand breaks.
The observed mutations originated primarily from large deletions in the postspermatogonial cells whereas other types of mutagenic mechanisms predominated in the spermatogonial cells.
This in vivo data is supported by in vitro studies showing that cell culture treatment with melphalan (at concentrations ranging from 0.1 to 25 μM) also induced DNA damage.
In addition, it induced aneuploidy and sex-linked recessive lethal mutations in Drosophila, and mutation in bacteria. It was positive with all strains in the Ames test at concentrations of 200 μg/plate and above. The mutagenic activity of melphalan was increased 3-fold in the presence of liver S9 metabolising preparations, which is unexpected since melphalan is not considered to need liver activation to produce a cytotoxic effect.
Carcinogenicity: Melphalan is a direct-acting alkylating agent that is carcinogenic via a genotoxic mechanism, which is sufficiently supported by animal studies.
Development of neoplastic tumours in mice reported following oral administration of melphalan at doses of 0.10-1.63 times the MRHD; in monkeys, the carcinogenic potential was observed at a dose of 0.16 times the MRHD.