Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity

Abstract

Summary:We studied the pharmacokinetics of intravenous busulfan (Bu) in children in order to further optimize intravenous Bu dosing in relation to toxicity and survival. A total of 31 children undergoing Bu-based conditioning for allogeneic SCT were enrolled in a study. The starting dose was 1.0 mg/kg (age o4 years) and 0.8 mg/kg (age X4 years), four doses per day during 4 days. Dose adjustment was allowed up to a maximum dose of 1.0 mg/kg per dose if the target area under the serum concentration-time curve (AUC) was not reached. Pharmacokinetic studies were performed after the first dose. Donor engraftment was established in 28 out of 31 patients. The average AUC after the first dose was the same in children o4 years as in children X4 years. Mean clearance was higher in children o4 years than in children X4 years. In 35% of all patients, total AUC was within the target AUC. The other children's AUCs were below the target range. No relationships were found between systemic exposure to Bu and toxicity or clinical outcome. We concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

“…Interestingly, among the patients we analyzed, 50% had C ss values below the lower target level limit, similar to other studies. 8,18,31 This may suggest that patients with the non-null GSTM1 genotype could receive a higher first dose. It remains to be seen in larger studies whether any of these genotypes may predict BU-related side effects.…”

“…18,29,30 Despite these improvements, inter-patient variability still exists and the percentage of patients reaching the target AUC after the first dose remains low. 8,18,26,31,32 Several factors have been identified to account for differences such as sex, weight, age or BSA. 4,26,33 In this paper, we examined whether the polymorphisms in the GSTA1, GSTM1 and GTP1 genes also contributed to this variability.…”

Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT

“…14 A one-compartment population model with linear elimination was formulated, based on a BU model developed for children by this group first in NONMEM 11 and after that in MW Pharm. 15 The calculated mean population pharmacokinetic parameters, clearance and half-life, were individualized according to the maximum a posteriori Bayesian fitting method. 16 AUC was calculated by dividing the administered dose by clearance.…”

Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant

“…In more recent studies that used i.v. BU as part of a myeloablative conditioning regimen, Tran et al 12 reported a 10% graft failure rate; Zwaveling et al 18,48 reported 10% using four times a day dosing and 22% using once a day dosing; Schechter et al 41 reported no graft failure in their cohort and Bartelink et al 49 reported 6%. It was not established in these recent studies whether there is a relationship between the AUC attained and the incidence of graft failure.…”

“…Hassan et al 47 reported a VOD incidence of 11% in pediatric patients who received liposomal BU twice a day for 4 days; Tran et al 12 reported no cases of VOD in 20 children who received i.v. BU four times a day for 4 days; Zwaveling et al 18,48 saw a VOD incidence of 26 and 6% after i.v. BU was given either four times or once a day for 4 days; Schechter et al 41 documented an 18% incidence of VOD after i.v.…”