Pharmaceutical group: Alkyl sulfonates. ATC code: L01AB01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Busulfan (1,4-butanediol dimethanesulfonate) is a bifunctional alkylating agent. Binding to DNA is believed to play a role in its mode of action, and di-guanyl derivatives have been isolated, but interstrand crosslinking has not been conclusively demonstrated.
The basis for the uniquely selective effect of busulfan on granulocytopoiesis is not fully understood. Although not curative, busulfan is very effective in reducing the total granulocyte mass, relieving the symptoms of disease and improving the clinical state of the patient. Busulfan has been shown to be superior to splenic irradiation when judged by survival times and maintenance of haemoglobin levels and is as effective in controlling spleen size.
Pharmacodynamic Effects: No information available.
Clinical Studies: No information available.
Pharmacokinetics: Absorption: The area under the curve (AUC) and peak plasma concentrations (Cmax) of busulfan have been shown to be linearly dose dependent. Following administration of a single 2 mg oral dose of busulfan, the AUC and Cmax of busulfan were 125±17 nanograms·h/ml and 28±5 nanograms/ml, respectively.
A lag time between busulfan administration and detection in the plasma of up to 2 h has been reported.
The bioavailability of oral busulfan shows large intra-individual variation ranging from 47% to 103% (mean 80%) in adults.
High-dose Treatment: Drug was assayed either using gas liquid chromatography with electron capture detection or by high-performance liquid chromatography (HPLC).
Following oral administration of high-dose busulfan (1 mg/kg every 6 h for 4 days), AUC and Cmax in adults are highly variable but have been reported to be 8260 nanograms·h/ml (range 2484 to 21090) and 1047 nanograms/ml (range 295 to 2558) respectively when measured by HPLC and 6135 nanograms·h/ml (range 3978 to 12304) and 1980 nanograms/ml (range 894 to 3800) respectively using gas chromatography.
Distribution: Busulfan is reported to have a volume of distribution of 0.64±0.12 L/kg in adults.
Busulfan given in high doses has been shown to enter the cerebrospinal fluid (CSF) in concentrations comparable to those found in plasma, with a mean CSF : plasma ratio of 1.3 : 1. The saliva : plasma distribution of busulfan was 1.1 : 1.
The level of busulfan bound reversibly to plasma proteins has been variably reported to be insignificant or approximately 55%. Irreversible binding of drug to blood cells and plasma proteins has been reported to be 47% and 32%, respectively.
Metabolism: Busulfan metabolism involves a reaction with glutathione, which occurs via the liver and is mediated by glutathione-S-transferase.
The urinary metabolites of busulfan have been identified as 3-hydroxysulpholane, tetrahydrothiophene 1-oxide and sulpholane, in patients treated with high-dose busulfan.
Elimination: Busulfan has a mean elimination half-life of between 2.3 and 2.8 h. Adult patients have demonstrated a clearance of busulfan of 2.4 to 2.6 ml/min/kg. The elimination half-life of busulfan has been reported to decrease upon repeat dosing suggesting that busulfan potentially increases its own metabolism.
Very little (1 to 2%) busulfan is excreted unchanged in the urine.
Special Populations: Children: The bioavailability of oral busulfan shows large intra-individual variation ranging from 22% to 120% (mean 68%) in children.
Plasma clearance is reported to be 2 to 4 times higher in children than in adults when receiving 1 mg/kg every 6 h for 4 days. Dosing children according to body surface area has been shown to give AUC and Cmax values similar to those seen in adults. The area under the curve has been shown to be half that of adults in children under the age of 15 years and a quarter of that of adults in children under 3 years of age.
Busulfan is reported to have a volume of distribution of 1.15±0.52 L/kg in children.
When busulfan is administered at a dose of 1 mg/kg every 6 h for 4 days, the CSF: plasma ratio has been shown to be 1.02:1. However, when administered at a dose of 37.5 mg/m2 every 6 h for 4 days the ratio was 1.39:1.
Obese Patients: Obesity has been reported to increase busulfan clearance. Dosing based on body surface area or adjusted ideal bodyweight should be considered in the obese.
Toxicology: Non-Clinical Information: Carcinogenesis, mutagenesis: Busulfan has been shown to be mutagenic in various experimental systems, including bacteria (Ames Salmonella test), fungi, Drosophila and cultured mouse lymphoma cells.
In vivo cytogenetic studies in rodents have shown an increased incidence of chromosome aberrations in both germ cells and somatic cells after busulfan treatment.
There is insufficient evidence from preclinical studies to determine whether busulfan has carcinogenic potential (see Precautions).
Reproductive Toxicology: There is evidence from animal studies that busulfan produces foetal abnormalities and adverse effects on offspring, including defects of the musculoskeletal system, reduced body weight and size, impairment of gonadal development and effects on fertility.
Busulfan interferes with spermatogenesis in experimental animals. Limited studies in female animals indicate busulfan has a marked and irreversible effect on fertility via oocyte depletion.