Busulfan disposition: The role of therapeutic monitoring in bone marrow transplantation induction regimens

High-dose busulfan is an important component of many bone marrow transplantation (BMT) preparative regimens. The dose-limiting toxicity of busulfan in BMT regimens is hepatic veno-occlusive disease (VOD), which occurs in approximately 20% to 40% of patients. We used a gas chromatography- electron capture detection assay and pharmacokinetic models to examine busulfan disposition in adults and children. Marked interpatient and intrapatient variability in busulfan disposition was observed in both patient populations. Part of the intrapatient variation appeared to be due to circadian changes in busulfan disposition. We also used gas chromatography- electron capture detection and pharmacokinetic models to assess whether excessive exposure to busulfan correlates with an increased risk of VOD. The area under the curve of time versus concentration (AUC) after the first dose of busulfan was measured in patients receiving a 16-dose course of busulfan as part of a BMT preparative regimen. In 27 patients who showed high AUCs (>1,500 μmol · min/L) after the first dose, the fifth through 16th doses of busulfan were decreased. Patients with high AUCs who did not receive dose adjustments had a 75% incidence of VOD. The incidence of VOD was only 18% in patients with high AUCs whose dose was adjusted on the basis of therapeutic monitoring, 5% for those not needing adjustment. These studies suggest that therapeutic monitoring can play an important role in decreasing the toxicity of BMT preparative regimens. Therapeutic monitoring also may improve treatment efficacy by identifying patients who are not receiving adequate drug exposure.