ons 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.
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.
Elimination
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.
Pharmacokinetic/pharmacodynamic relationships
The literature on busulfan suggests a therapeutic window between 900 and 1500 µmol/L.minute for AUC. During clinical trials with intravenous busulfan, 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).
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 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.
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 non-malignant) 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 as detailed in section 4.2 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 |
