Hanen Marsit1,2, Michaël Philippe3, Michael Neely4, Teresa Rushing5, Yves Bertrand3, Michel Ducher6,7, Vincent Leclerc6,7, Jérôme Guitton7,8, Nathalie Bleyzac6,7, Sylvain Goutelle9,10,11. 1. Univ Lyon, Université Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France. 2. Université de Monastir, Faculté de Pharmacie, Monastir, Tunisia. 3. Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France. 4. Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious Diseases, Children's Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA. 5. Pharmacy Department, Children's Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA. 6. Service de Pharmacie, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France. 7. Univ Lyon, Université Lyon 1, EMR 3738 PK/PD Modeling in Oncology and Hematology, Lyon, France. 8. Laboratoire de Pharmacologie et Toxicologie, Hospices Civils de Lyon, Groupement Hospitalier Sud, Lyon, France. 9. Univ Lyon, Université Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France. sylvain.goutelle@chu-lyon.fr. 10. Service de Pharmacie, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France. sylvain.goutelle@chu-lyon.fr. 11. Univ Lyon, Université Lyon 1, ISPB, Faculté de Pharmacie de Lyon, Lyon, France. sylvain.goutelle@chu-lyon.fr.
Abstract
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.
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.
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