High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequentl
y used in preparative regimens for haemopoietic stem cell transplantation (
HSCT). Busulfan is well absorbed after oral administration, exhibits low pr
otein binding and is metabolised through conjugation with glutathione to fo
rm a thiophenium ion. At a given dose, there is considerable variability in
the systemic exposure of busulfan, typically expressed as area under the p
lasma concentration-time curve (AUC) or average concentration at steady sta
te (C-SS) Relative to that in adolescents and adults, patients less than 4
years of age have an increased apparent oral clearance (CL/F) of busulfan a
nd a higher conjugation rate of busulfan with glutathione in the enterocyte
.
Several investigators have identified relationships between busulfan C-SS a
nd outcome in patients undergoing HSCT. Busulfan concentration-response rel
ationships are regimen-, age- and disease-dependent. The busulfan/cyclophos
phamide (BU/CY) regimen is the only regimen for which substantial concentra
tion-outcome data exist. Generally, the risk of hepatic veno-occlusive dise
ase is increased with busulfan C-SS > 900 mu g/L
The impact of busulfan C-SS on veno-occlusive disease may be influenced by
the age of the patient and the dose of cyclophosphamide. Lower rates of rel
apse in chronic myelogenous leukaemia occur in patients with a busulfan C-S
S > 917 mu g/L without an increased risk of toxicity. Busulfan C-SS is also
related to the engraftment rate in children, and escalating busulfan doses
to achieve a target C-SS > 600 mu g/L improves graft retention.
Therapeutic drug monitoring of busulfan should be performed to maximise the
likelihood of engraftment and minimise the risk of toxicity and relapse in
HSCT patients receiving the BU/CY preparative regimen.