Bufatas Mechanism of Action

Pharmacotherapeutic group: Alkyl sulfonates. ATC code: L01AB01.
Pharmacology: PHARMACODYNAMICS: Mechanism of action: 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.
Clinical efficacy and safety: Busulfan in combination with cyclophosphamide: In adults: Documentation on the safety and efficacy of busulfan in combination with cyclophosphamide in the BuCy2 regimen prior to conventional allogeneic and/or autologous HPCT derives from two clinical trials (OMC-BUS-4 and OMC-BUS-3).
Diseases included were acute leukeaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic myelogenous leukemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma, and myelodysplastic syndrome.
Paediatric population: Documentation of the safety and efficacy of busulfan in combination with cyclophosphamide in the BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/or autologous HPCT derives from clinical trial F60002 IN 101 G0.
The patients received the dosing mentioned in Dosage & Administration.
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x10⁹/l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15 days) in autologous patients. All children engrafted. There is no primary or secondary graft rejection. 93% of allogenic patients showed complete chimerism. There was no regimen-related death through the first 100-day post-transplant and up to one year post-transplant.
Busulfan in combination with fludarabine (FB): In adults: Documentation on the safety and efficacy of busulfan in combination with fludarabine (FB) prior to allogenic HPCT derives from the literature review of 7 published studies involving 731 patients with myeloid and lymphoid malignancies reporting the use of intravenous busulfan infused once daily instead of four doses per day.
Patients received a conditioning regimen based on the administration of fludarabine immediately followed by single daily dose of 3.2 mg/kg busulfan over 2 or 3 consecutive days. Total dose of busulfan per patient was between 6.4 mg/kg and 9.6 mg/kg.
The FB combination allowed sufficient myeloablation modulated by the intensity of conditioning regimen through the variation of number of days of busulfan infusion. Fast and complete engraftment rates in 80-100% of patients were reported in the majority of studies. A majority of publications reported a complete donor chimerism at day+30 for 90-100% of patients. The long-term outcomes confirmed that the efficacy was maintained without unexpected effects.
PHARMACOKINETICS: The pharmacokinetics of busulfan has been investigated. The information presented on biotransformation and elimination is based on oral busulfan.
Pharmacokinetics in adults: Absorption: 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.
Distribution: 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%.
Biotransformation: Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S transferase 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.
Linearity: 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.
Pharmacokinetic/pharmacodynamic relationships: 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.
Special populations: Hepatic or renal impairment: 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 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.
Paediatric population: 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.
The recommended posology for children as detailed in Dosage & Administration 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.
Pharmacokinetic/pharmacodynamic relationships: 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.