Tiago Nava1,2,3,4, Nastya Kassir5, Mohamed Aziz Rezgui1, Chakradhara Rao Satyanarayana Uppugunduri2,3, Patricia Huezo-Diaz Curtis2,3, Michel Duval1,6, Yves Théoret1,7,8, Liane E Daudt4, Catherine Litalien7,6, Marc Ansari2,3, Maja Krajinovic1,7,8, Henrique Bittencourt1,6. 1. Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada. 2. CANSEARCH Research Laboratory, Department of Pediatrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 3. Department of Pediatrics, Onco-Hematology Unit, University Hospital of Geneva, Geneva, Switzerland. 4. Post Graduate Program in Child and Adolescent Health, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. 5. Certara Strategic Consulting, Montreal, Quebec, Canada. 6. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. 7. Clinical Pharmacology Unit, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada. 8. Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
Abstract
AIMS: The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism. METHODS: Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.1-20) who received intravenous busulfan during the conditioning regimen prior to stem cell transplantation. Weight, sex, baseline disease (malignant vs. non-malignant), age, conditioning regimen and GSTA1 diplotypes were evaluated as covariates of pharmacokinetic parameters by using nonlinear mixed effects analysis. The ability to achieve the target AUC24h (3600-6000 μM min-1 ) was assessed by estimating the first dose based on the present PopPK model and by comparing the results with other available models in children. RESULTS: A one-compartment model with first-order elimination best described the data. Allometric scaling of weight and a factor of busulfan metabolism maturation were included in the base model. GSTA1 diplotypes were found to be a significant covariate of busulfan clearance, which was 7% faster in rapid metabolizers and 12% slower in poor metabolizers, in comparison with normal ones. Busulfan doses calculated using the parameters of the proposed PopPK model were estimated to achieve the target AUC in 85.2% of the cases (95% CI 78.7-91.7%). CONCLUSION: This is the first PopPK for busulfan that successfully incorporated GSTA1 genotype in a paediatric population. Its use may contribute to better prediction of busulfan exposure in children and adolescents since the first dose, by tailoring the dose according to the individual metabolic capacity.
AIMS: The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism. METHODS:Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.1-20) who received intravenous busulfan during the conditioning regimen prior to stem cell transplantation. Weight, sex, baseline disease (malignant vs. non-malignant), age, conditioning regimen and GSTA1 diplotypes were evaluated as covariates of pharmacokinetic parameters by using nonlinear mixed effects analysis. The ability to achieve the target AUC24h (3600-6000 μM min-1 ) was assessed by estimating the first dose based on the present PopPK model and by comparing the results with other available models in children. RESULTS: A one-compartment model with first-order elimination best described the data. Allometric scaling of weight and a factor of busulfan metabolism maturation were included in the base model. GSTA1 diplotypes were found to be a significant covariate of busulfan clearance, which was 7% faster in rapid metabolizers and 12% slower in poor metabolizers, in comparison with normal ones. Busulfan doses calculated using the parameters of the proposed PopPK model were estimated to achieve the target AUC in 85.2% of the cases (95% CI 78.7-91.7%). CONCLUSION: This is the first PopPK for busulfan that successfully incorporated GSTA1 genotype in a paediatric population. Its use may contribute to better prediction of busulfan exposure in children and adolescents since the first dose, by tailoring the dose according to the individual metabolic capacity.
Authors: Rosa F Yeh; Matthew A Pawlikowski; David K Blough; George B McDonald; Paul V O'Donnell; Andrew Rezvani; H Joachim Deeg; Jeannine S McCune Journal: Biol Blood Marrow Transplant Date: 2011-07-04 Impact factor: 5.742
Authors: M Ansari; M A Rezgui; Y Théoret; C R S Uppugunduri; S Mezziani; M-F Vachon; C Desjean; J Rousseau; M Labuda; C Przybyla; M Duval; M Champagne; C Peters; H Bittencourt; M Krajinovic Journal: Bone Marrow Transplant Date: 2013-01-07 Impact factor: 5.483
Authors: A M Bolinger; A B Zangwill; J T Slattery; L J Risler; D H Sultan; D V Glidden; D Norstad; M J Cowan Journal: Bone Marrow Transplant Date: 2001-12 Impact factor: 5.483
Authors: Ji Won Lee; Hyoung Jin Kang; Seung Hwan Lee; Kyung-Sang Yu; Nam Hee Kim; Yen Ju Yuk; Mi Kyoung Jang; Eun Jong Han; Hyery Kim; Sang Hoon Song; Kyung Duk Park; Hee Young Shin; In-Jin Jang; Hyo Seop Ahn Journal: Biol Blood Marrow Transplant Date: 2011-12-07 Impact factor: 5.742
Authors: I H Bartelink; E M L van Reij; C E Gerhardt; E M van Maarseveen; A de Wildt; B Versluys; C A Lindemans; M B Bierings; Jaap Jan Boelens Journal: Biol Blood Marrow Transplant Date: 2013-12-04 Impact factor: 5.742
Authors: Maria Antonietta DE Ioris; Benedetta Contoli; Alessandro Jenkner; Maria Debora DE Pasquale; Annalisa Serra; Luigi DE Sio; Rosanna Pessolano; Maria Carmen Garganese; Alessandro Crocoli; Teresa Corneli; Renata Boldrini; Aurora Castellano Journal: Anticancer Res Date: 2012-12 Impact factor: 2.480
Authors: F Bernard; P Auquier; I Herrmann; A Contet; M Poiree; F Demeocq; D Plantaz; C Galambrun; V Barlogis; J Berbis; F Garnier; N Sirvent; J Kanold; P Chastagner; H Chambost; G Michel Journal: Bone Marrow Transplant Date: 2014-02-17 Impact factor: 5.483
Authors: Donna A Wall; Ka Wah Chan; Michael L Nieder; Robert J Hayashi; Andrew M Yeager; Richard Kadota; Donna Przepiorka; Khaled Mezzi; Morris Kletzel Journal: Pediatr Blood Cancer Date: 2010-02 Impact factor: 3.167
Authors: Adrin Dadkhah; Sebastian Georg Wicha; Nicolaus Kröger; Alexander Müller; Christoph Pfaffendorf; Maria Riedner; Anita Badbaran; Boris Fehse; Claudia Langebrake Journal: Pharmaceutics Date: 2022-05-27 Impact factor: 6.525
Authors: Adrin Dadkhah; Dzenefa Alihodzic; Astrid Broeker; Nicolaus Kröger; Claudia Langebrake; Sebastian G Wicha Journal: Pharm Res Date: 2021-10-18 Impact factor: 4.200