Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children
Clinical pharmacokinetics. 2020
BACKGROUND Busulfan therapeutic drug monitoring (TDM) is necessary to better achieve the target exposure in children before hematopoietic stem cell transplantation (HSCT). However, TDM-based dosing may be challenging if intra-individual pharmacokinetic variability (also denoted inter-occasion variability [IOV]) occurs during therapy. OBJECTIVES The objectives of this study were to describe and quantify busulfan IOV in children, and to investigate its potential determinants. METHODS We performed a new analysis of published data from children who received intravenous busulfan over 4 days before HSCT. We calculated individual pharmacokinetic parameters on each day of therapy using a published population pharmacokinetic model of busulfan and analyzed their changes. Population estimation of IOV was also performed with non-linear mixed effects (NLME) modeling. Potential predictors of significant decrease in busulfan clearance (CL) were assessed by using machine learning approaches. RESULTS IOV could be assessed in 136 children. Between day (D) 1 and D2, most patients (80%) experienced a decrease in busulfan CL, with a median change of - 7.9%. However, both large decreases (minimum, - 48.5%) and increases in CL (maximum, + 44%) were observed. Over D1-D3 of therapy, mean CL significantly decreased (- 15%), with a decrease of ≥ 20% in 22% of patients. Some patients also showed unstable CL from day to day. NLME modeling of IOV provided a coefficient of variation of 10.6% and 13.1% for volume of distribution (Vd) and CL, respectively. Some determinants of significant decreases in busulfan CL were identified, but predictive performance of the models was limited. CONCLUSIONS Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing.
Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children
Bone marrow transplantation. 2018
Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration-Cmax, area under the concentration-time curve-AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children.
Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children
Bone Marrow Transplantation. 2016;51(1):72-8
Busulfan, the corner stone of hematopoietic stem cell transplantation regimens, has a narrow therapeutic window. Therapeutic drug monitoring (TDM)-guided dosing to reach the conventional area under the concentration-time curve (AUC) target range of 900-1500mumolmin/L is associated with better outcomes. We report our experience with busulfan TDM in a large cohort of children. The aims were to investigate the relevance of using a more restricted therapeutic range and investigate the association between busulfan therapeutic range and clinical outcome. This study includes 138 children receiving 16 doses of intravenous busulfan, with the first dose assigned based on weight and doses adjusted to a local AUC target range of 980-1250mumolmin/L. Busulfan TDM combined with model-based dose adjustment was associated with an increased probability of AUC target attainment, for both target range: 90.8% versus 74.8% for the conventional target range and 66.2% versus 43.9% for the local target range (P<0.001). The median follow-up was 56.2 months. Event-free survival was 88.5%, overall survival was 91.5% and veno-occlusive disease occurred in 18.3% of patients. No difference was observed for clinical outcomes depending on the selected target range. Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving target attainment, but using a restricted target range has no impact on clinical outcomes.
Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis
Bone Marrow Transplantation. 2016;51(5):698-704
There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration 120ng/mL versus 43% with concentration >120ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) 10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.