Pharmacologically-guided dose adjustment of busulfan in high-dose chemotherapy regimens: rationale and pitfalls (review)

High-dose busulfan is used in conditioning regimens before allogeneic or autologous bone marrow transplantation (BMT) in adults and children. During the last six years, several studies have established the wide inter- and intrapatient variability of high-dose busulfan disposition. Clearance rate ranges from 0.8 to 20 ml/min/kg. Some factors of variability have been identified: age, alteration in hepatic functions, disease, circadian rhythmicity, drug interactions. Using a fixed dose of busulfan, wide interpatient variability in systemic exposure is thus expected, with eventual consequences on toxicity and efficacy. In adults, a pharmacodynamic relationship between a high busulfan systemic exposure and the occurrence of hepatic veno-occlusive disease (HVOD) has been established. A prospective controlled study demonstrated that busulfan dose-adjustment decreased the morbidity and mortality of HVOD in adults. So far, pharmacodynamic studies in children have failed to establish a toxic level. The present paper analyses the rationale for busulfan dose adjustment, and focuses on the eventual pitfalls that may jeopardize its reliability (drug absorption, chronopharmacology, drug interaction within the conditioning regimen, complex pathophysiology of HVOD). Further pharmacodynamic studies are required to establish a minimum therapeutic threshold in systemic exposure for bone marrow engraftment, especially in children undergoing HLA-compatible or incompatible allogeneic BMT for non malignant disease. The definition of a therapeutic window according to the disease and the type of BMT, along with the development of iv-busulfan, will allow accurate and effective pharmacologically-guided dose adjustment of high-dose busulfan. By the end of the century, busulfan plasma level monitoring and dose adjustment at the individual level may improve the outcome of patients undergoing BMT.