Chemical formula: C₆H₁₄O₆S₂ Molecular mass: 246.302 g/mol PubChem compound: 2478
Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.
The pharmacokinetics of busulfan has been investigated. The information presented on biotransformation and elimination is based on oral busulfan.
The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a 2-hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure was observed when comparing plasma concentrations in adult patients receiving oral and intravenous busulfan at 1 mg/kg and 0.8 mg/kg respectively. Low inter (CV=21%) and intra (CV=12%) patient variability on busulfan exposure was demonstrated through a population pharmacokinetic analysis, performed on 102 patients.
Terminal volume of distribution Vz ranged between 0.62 and 0.85 l/kg.
Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity. Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, was about 32%.
Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-Stransferase mediated). The glutathione conjugate is then further metabolised in the liver by oxidation. None of the metabolites is thought to contribute significantly to either efficacy or toxicity.
Total clearance in plasma ranged 2.25 – 2.74 ml/minute/kg. The terminal half-life ranged from 2.8 to 3.9 hours.
Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged busulfan. Elimination in faeces is negligible. Irreversible protein binding may explain the incomplete recovery. Contribution of long-lasting metabolites is not excluded.
The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfan up to 1 mg/kg.
Compared to the four times a day regimen, the once-daily regimen is characterized by a higher peak concentration, no drug accumulation and a wash out period (without circulating busulfan concentration) between consecutive administrations. The review of the literature allows a comparison of PK series performed either within the same study or between studies and demonstrated unchanged dose-independent PK parameters regardless the dosage or the schedule of administration. It seems that the recommended intravenous busulfan dose administered either as an individual infusion (3.2 mg/kg) or into 4 divided infusions (0.8 mg/kg) provided equivalent daily plasma exposure with similar both inter-and intrapatient variability. As a result, the control of intravenous busulfan AUC within the therapeutic windows is not modified and a similar targeting performance between the two schedules was illustrated.
The literature on busulfan suggests a therapeutic AUC window between 900 and 1500 µmol/L.minute per administration (equivalent to a daily exposure between 3600 and 6000 µmol/L.minute). During clinical trials with intravenous busulfan administered as 0.80 mg/kg four-times daily, 90% of patients AUCs were below the upper AUC limit (1500 µmol/L.minute) and at least 80% were within the targeted therapeutic window (900-1500 µmol/L.minute). Similar targeting rate is achieved within the daily exposure of 3600 – 6000 µmol/L.minute following the administration of intravenous busulfan 3.2 mg/kg once daily.
The effects of renal dysfunction on intravenous busulfan disposition have not been assessed. The effects of hepatic dysfunction on intravenous busulfan disposition have not been assessed. Nevertheless the risk of liver toxicity may be increased in this population. No age effect on busulfan clearance was evidenced from available intravenous busulfan data in patients over 60 years.
A continuous variation of clearance ranging from 2.49 to 3.92 ml/minute/kg has been established in children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h. Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively. A population pharmacokinetic analysis has been performed in a cohort of 205 children adequately distributed with respect to bodyweight (3.5 to 62.5 kg), biological and diseases (malignant and nonmalignant) characteristics, thus representative of the high heterogeneity of children undergoing HPCT. This study demonstrated that bodyweight was the predominant covariate to explain the busulfan pharmacokinetic variability in children over body surface area or age.
The recommended posology for children enabled over 70% up to 90% of children ≥ 9 kg in achieving the therapeutic window (900-1500 µmol/L.minute). However a higher variability was observed in children < 9 kg leading to 60% of children achieving the therapeutic window (900-1500 µmol/L.minute). For the 40% of children < 9 kg outside the target, the AUC was evenly distributed either below or above the targeted limits; i.e. 20% each < 900 and > 1500 µmol/L.min following 1 mg/kg. In this regard, for children < 9 kg, a monitoring of the plasma concentrations of busulfan (therapeutic drug monitoring) for dose-adjustment may improve the busulfan targeting performance, especially in extremely young children and neonates.
The successful engraftment achieved in all patients during phase II trials suggests the appropriateness of the targeted AUCs. Occurrence of VOD was not related to overexposure. PK/PD relationship was observed between stomatitis and AUCs in autologous patients and between bilirubin increase and AUCs in a combined autologous and allogeneic patient analysis.
Busulfan is mutagenic and clastogenic. Busulfan was mutagenic in Salmonella typhimurium, Drosophila melanogaster and barley. Busulfan induced chromosomal aberrations in vitro (rodent and human cell) and in vivo (rodents and humans). Various chromosome aberrations have been observed in cells from patients receiving oral busulfan.
Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism of action. On the basis of human data, busulfan has been classified by the IARC as a human carcinogen. WHO has concluded that there is a causal relationship between busulfan exposure and cancer. The available data in animals support the carcinogenic potential of busulfan. Intravenous administration of busulfan to mice significantly increased the incidences of thymic and ovarian tumours.
Busulfan is a teratogen in rats, mice and rabbits. Malformations and anomalies included significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in testes and ovaries. Busulfan was shown to cause sterility in rodents. Busulfan depleted oocytes of female rats, and induced sterility in male rats and hamster.
Repeated doses of DMA produced signs of liver toxicity, the first being increases in serum clinical enzymes followed by histopatological changes in the hepatocytes. Higher doses can produce hepatic necrosis and liver damage can be seen following single high exposures.
DMA is teratogenic in rats. Doses of 400 mg/kg/day DMA administered during organogenesis caused significant developmental anomalies. The malformations included serious heart and/or major vessels anomalies: a common truncus arteriosis and no ductus arteriosis, coarctation of the pulmonary trunk and the pulmonary arteries, intraventricular defects of the heart. Other frequent anomalies included cleft palate, anasarca and skeletal anomalies of the vertebrae and ribs. DMA decreases fertility in male and female rodents. A single s.c. dose of 2.2 g/kg administered on gestation day 4 terminated pregnancy in 100% of tested hamster. In rats, a DMA daily dose of 450 mg/kg given to rats for nine days caused inactive spermatogenesis.
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