Plasma concentration monitoring of busulfan: does it improve clinical outcome?
High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/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.
McCune
J S
JS
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Gibbs
J P
JP
Slattery
J T
JT
D000328:Adult; D000367:Age Factors; D000818:Animals; D002066:Busulfan / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods*; D006084:Graft Rejection / Q000188:drug therapy / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D002066:Busulfan