Therapeutic Drug Monitoring (TDM) of IV Busulfan in Patients with Severe Obesity.

It has been previously reported that increases in relapse and graft rejection can be associated with a low busulfan area under the curve (AUC) and hepatic toxicities are associated with a high AUC. This has lead to strategies to adjust busulfan dosing to achieve a target AUC. A retrospective analysis was performed in patients with severe obesity, defined as a Body Mass Index (BMI) greater than 40, to evaluate the reliability of IV busulfan dosed using the package insert dosing strategy to reach a targeted AUC. The study included 11 females and 8 males who received IV busulfan as part of their hematopoietic progenitor cell transplant preparative regimen. There were 11 autologous and 8 allogeneic transplants for lymphoma (10) and leukemia (9). The mean and median ages were 38 and 41 years (range 19–51). The mean and median BMIs for this population were 47.8 and 46.2 (range 40.4–62.7). The mean and median weights were 139.5 kg and 142.5 kg (range 107–192.3). TDM was performed with the first dose of busulfan along with subsequent dosage adjustments to achieve a target AUC of 1150–1350 micromol X min/L. Busulfex package insert dosing recommendations are for 16 doses of 0.8 mg/kg (12.8 mg/kg) using an adjusted ideal body weight (AIBW) for obese patients. AIBW = 0.25 × (actual weight − ideal body weight) + ideal body weight. Using the AIBW dosing, the mean starting dose to actual body weight ratio was 0.48 mg/kg (range 0.40–0.55 mg/kg). Based on the AUC analysis, the predicted mean AUC using the AIBW dosing was 972 (range 702–1356). Six AUCs were below 900, 10 AUCs were above 900 but below 1150, 2 AUCs were within the target range and 1 AUC was greater than 1350. Thirteen of the patients had repeat AUC analyses following a subsequent dose to confirm that the dose adjustments achieved the targeted AUCs. Seven of these patients had further dose adjustments following the repeat AUC analysis. Five patients with a busulfan mean half-life of 235 minutes (range 218–247 minutes) had higher AUCs than the rest of the group. The mean and median AUCs for these 5 patients were 1177 and 1223 (range 997–1357). The remaining 14 patients with a mean busulfan half-life of 177 minutes (range 151–201) had mean and median AUCs of 899 and 903 (range 702–1105). The total therapy delivered ranged from 12.7 to 21.4 mg/kg based on the AIBW. When calculated on actual weight, the range was 6.9 to 11.24 mg/kg.

Conclusion: The AIBW dosing strategy of IV busulfan is inadequate to achieve the targeted AUC of 1150–1350 in severely obese patients. Severely obese patients require dose increases in the majority of cases, while those with delayed clearance could be overdosed if higher doses are administered without TDM. Severely obese patients require TDM and the majority will require dosage adjustments to administer IV busulfan in the targeted therapeutic range.