Background Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. Methods In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. Results 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication. Interpretation These results demonstrate that improved clinical outcomes may be achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new validated pharmacokinetic-model for all indications.

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Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.

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In this study, a bioanalytical method, PK model, and limited sampling model were developed and validated. Furthermore, PK parameters of 20 pediatric patients were analyzed, demonstrating an interpatient variability in area under the curve of 14.5%. This study demonstrates the essential developments in the optimization of treosulfan therapy based on PK data.

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.

Because of intra- and interindividual variability, bioavailability, and pharmacokinetics of busulfan (Bu) in children, oral busulfan without therapeutic drug monitoring (TDM) is assumed to be associated with higher graft failure rates as well as higher toxicity (eg, veno-occlusive disease [VOD]). This study compares the outcome of hematopoietic stem cell transplantation (HSCT) of 2 groups: 1) 30 patients who received myeloablation with once-daily intravenous (i.v.) dose-targeted busulfan (BUdtIV) based on TDM and 2) 30 patients who received the current practice of untargeted oral busulfan (BUPO). Patients received a 3-hour infusion of Bu at a first dose of 120 mg/m(2) (age >or=1 year) or 80 mg/m(2) (<1 year), or BUPO 1 mg/kg 4 times daily. Both regimens were continued for 4 days. The target area under the curve (AUC) was defined as 17,500 microg *h/l. BUdtIV resulted in higher event-free survival (EFS) and survival rates compared to BUPO (EFS: 30% versus 83%, P < .001, survival: 53% versus 83%, P = .016). BUdtIV was associated with more cases of VOD. TDM was feasible in routine clinical practice. The results show that i.v. Bu using TDM is preferable over oral Bu in children undergoing allogeneic stem cell transplantation, especially in those at high risk for graft failure/relapse.