The impact of age and obesity on plasma busulfan levels

IV busulfan is an alternative to oral busulfan in myeloablative regimens prior to hematopoietic stem cell transplantation (HSCT). Compared to oral busulfan which has variable bioavailability, IV busulfan assures consistent drug delivery and may be associated with a lower incidence of regimen-related toxicity. We were interested in the effect of the type of body weight calculation used for dosing busulfan on plasma busulfan levels. We investigated the pharmacokinetic data from 58 sequential patients (age 7m to 67y) who received IV busulfan. In addition, the pharmacokinetic data for 11 patients who were obese or under weight who received oral busulfan during the study period were also reviewed. Patients received IV busulfan (0.8 mg/kg), or oral busulfan (1 mg/kg). Patients whose actual weight exceeded 140% of their ideal body weight were dosed according to ideal [n=12] or adjusted [n=29] body weight. The target Css range for all patients was 600–900 ng/ml. Plasma busulfan Css was measured at a single reference laboratory by gas chromatography and mass spectrometry. Based on the pharmacokinetic result, remaining busulfan doses were adjusted to achieve the desired Css target when averaged over the 4-day dosing period. There was a significant difference in mean Css values between the IV and oral busulfan groups (727 ng/ml vs 986 ng/ml respectively) (p<0.001); furthermore there was less variability in the Css for the IV group compared to the oral group (p=0.01). When IV busulfan patients were analyzed, a significant difference was observed among mean Css values of the actual, ideal, and adjusted ideal body weight groups (658 ng/ml, 707 ng/ml, and 797 ng/ml) (p=0.01). Consistent with other studies, we found an inverse association between the age and busulfan clearance in IV busulfan group (p=0.004). In addition, 6/9 patients between the age of 1 to 10 years had Css below the minimum target. In this study, patients from 1 to 10 were all dosed by actual body weight. In conclusion, use of IV busulfan produces a narrower range of Css values. Both age and the choice of body weight calculation for dosing impacts plasma busulfan levels. Consideration should be given to increase dosing for children <10 years old. Both adjusted and ideal body weight calculations led to Css values in the target range. The use of ideal rather than adjusted ideal body weight for dosing obese patients yielded Css values similar to that achieved when using actual body weight for non-obese patients.