A decision support tool to find the best cyclosporine dose when switching from intravenous to oral route in pediatric stem cell transplant patients
European journal of clinical pharmacology. 2020
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.
Medication adherence after pediatric allogeneic stem cell transplantation: Barriers and facilitators
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2019;38:1-7
PURPOSE Immunosuppressive therapy following pediatric hematopoietic stem cell transplantation is essential for the patient's prognosis, as the antibioprophylaxis and the isolation measures. But medication adherence is suboptimal for children and adolescents, from 52 to 73% in literature. The aim of this study is to provide an understanding of medication adherence after pediatric allogeneic stem cell transplantation (SCT), by identifying facilitators and barriers. METHOD Semi-structured interviews were conducted by a pharmacist with caregivers and healthcare providers in a pediatric centre. Four topics were discussed: transplantation, post-transplantation therapies, caregivers' experience and the healthcare system. Interviews were audiotaped, transcribed and analysed by inductive approach. FINDINGS Semi-structured interviews with 15 caregivers and 21 healthcare providers identified factors of medication adherence and hygiene measures. The long-term nature of therapy and difficult transitions of care were identified as major barriers. Recognizing the benefits of medication and parental involvement are facilitators. Furthermore, caregivers expressed the need to take into consideration the family entity. They would like also to receive earlier information from healthcare providers before hospital discharge. Those needs were not always identified by healthcare providers. CONCLUSION This analysis revealed barriers and facilitators to the medication adherence and to the care. It demonstrated similarities and differences between caregivers and healthcare providers' perceptions and has thereby initiated an improvement process of the healthcare system. As part of this process, medical and paramedical healthcare providers at this French pediatric centre are currently working on a support program for post-alloSCT hospital-home transition.
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.
Bayesian Networks: A New Approach to Predict Therapeutic Range Achievement of Initial Cyclosporine Blood Concentration After Pediatric Hematopoietic Stem Cell Transplantation
Drugs in R&D. 2018
BACKGROUND Pediatric hematopoietic stem cell transplantation (HSCT) allows the treatment of numerous diseases, both malignant and non-malignant. Cyclosporine, a narrow therapeutic index drug, is the major immunosuppressant used to prevent graft-versus-host disease (GVHD), but may also cause severe adverse effects in case of overdosing. OBJECTIVE The objective of this study is to predict the initial cyclosporine residual blood concentration value after pediatric HSCT, and consequently the dose necessary to reach the therapeutic range, using a mathematical individual predictive model. METHODS Clinical and biological data collected from the graft infusion for 2 months after transplantation in 155 pediatric patients undergoing HSCT between 2008 and 2016 were used to generate synthetic data for 1000 subjects which were used to build a Bayesian network model. We compared the characteristics and sensitivity to clinical or biological missing data of this model with four other methods. RESULTS The tree-augmented Naive Bayesian network showed the best characteristics, with no missing data (area under the curve of the receiving operator characteristics curve [AUC-ROC] of 0.89 +/- 0.02), 18.9 +/- 2.6% of patients misclassified, and positive and negative predictive values of 85.9 +/- 3.4% and 74.2 +/- 5.1%, respectively, and this trend is found in the synthetic dataset from no to 10% missing data. The most relevant variables that could influence whether the initial residual cyclosporine concentration is in the therapeutic range are the last dose before measurement and the mean dose before measurement. CONCLUSIONS We developed and cross-validated an online Bayesian network to predict the first cyclosporine concentration after pediatric HSCT. This model allows simulation of different dosing regimens, and enables the best dosing regimen to reach the therapeutic range immediately after transplantation to be found, minimizing the risk of adverse effects and GVHD occurrence.
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.
Impact of a change in protected environment on the occurrence of severe bacterial and fungal infections in children undergoing hematopoietic stem cell transplantation
European Journal of Haematology. 2016;97(1):70-7
BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition. OBJECTIVE We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods. METHODS The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn. RESULTS Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63). CONCLUSION The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life. Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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.