Optimization of high-dose busulfan dosing in bone marrow transplant patients

Abstract

Objective. To review the pharmacokinetics profile of (HD-BU) high-dose busulfan, review published phar macodynamic relationships of high-dose busulfan and discuss clinical considerations of monitoring patients receiving high-dose busulfan. Data Sources. A MEDLINE search of articles published from 1985 to 1996 and a Cancerlit search of articles published from 1988 to 1996, using the Mesh headings "Busulfan (subheading: pharmacokinetics)," "Bone Marrow Transplantation" and "Hepatic Veno occlusive Disease." Study Selection. All human trials evaluating the pharmacokinetic profile and the pharmacodynamic relationships of high-dose busulfan in bone marrow transplant patients. Data Synthesis. Busulfan disposition has been extensively studied in both children and adults receiv ing high doses followed by stem cell rescue. Sample sizes ranged from 7 to 28 patients, with patients ranging from 0.3 to 60 years of age. Busulfan total doses ranged from 14 mg/kg to 640 mg/m2. A large interpatient variability has been reported in busulfan pharmacokinetics parameters for both children and adults. In adults, the maximum concentration (Cmax) achieved after the first oral dose of HD-BU ranged from 249 to 1512 ng/mL, the apparent volume of distribution (Vd) ranged from 0.56 to 0.66 L/kg, the total plasma clearance (CL) of busulfan ranged from 2.49 to 3.26 mL/min/kg, and the area under the time versus concentration curve (AUC) ranged from 103 to 21,120 ng h/mL. In children, the Cmax ranged from 577 to 1258 ng/mL, the Vd ranged from 0.74 to 1.42 L/kg, the CL of busulfan ranged from 3.26 to 8.91 mL/min/kg, and the AUC ranged from 309 to 13,129 ng h/mL. Several investigators have reported in creased busulfan CL, larger Vd and lower Cmax in children as compared to adults. In addition, children have lower AUCs as compared with adults when administered a fixed busulfan dose based on body weight. Lower busulfan AUCs in children appear to be the result of an increased systemic clearance and a larger volume of distribution as compared to adults. In adults, HD-BU systemic exposure have been corre lated to efficacy and toxicity in some studies; no prospective studies in children have established a clear role for routinely monitoring busulfan concen trations. Conclusions. Although routine monitoring with dosage adjustment of busulfan is probably warranted in some patients with extremely high or low busulfan plasma concentrations, clinical studies should con tinue to further define a therapeutic range for HD-BU.