Model-Informed Precision Dosing of Intravenous Busulfan in Thai Pediatrics Undergoing Hematopoietic Stem Cell Transplantation.
Journal
Therapeutic drug monitoring
ISSN: 1536-3694
Titre abrégé: Ther Drug Monit
Pays: United States
ID NLM: 7909660
Informations de publication
Date de publication:
14 May 2024
14 May 2024
Historique:
received:
01
12
2023
accepted:
26
01
2024
medline:
17
5
2024
pubmed:
17
5
2024
entrez:
17
5
2024
Statut:
aheadofprint
Résumé
Conditioning bifunctional agent, busulfan, is commonly used on children before hematopoietic stem cell transplantation. Currently, at the Ramathibodi hospital, Bangkok, Thailand, initial dosing is calculated according to age and body surface area, and 7 samples per day are used for therapeutic drug monitoring (TDM). This study aimed to identify the best strategies for individual dosages a priori from patient characteristics and a posteriori based on TDM. The pharmacokinetic data set consisted of 2018 plasma concentrations measured in 135 Thai (n = 135) pediatric patients (median age = 8 years) and were analyzed using a population approach. Body weight, presence of malignant disease, and genetic polymorphism of Glutathione S-transferase Alpha-1 (GSTA1) were predictors of clearance. The optimum sampling times for TDM concentration measurements were 0.25, 2, and 5 hours after a 3-hour infusion. This was sufficient to obtain a Bayesian estimate of clearance a posteriori. Simulations showed the poor performance of a priori formula-based dose calculations with 90% of patients demonstrating a 69%-151% exposure interval around the target. This interval shrank to 85%-124% if TDM was carried out only at day 1 and to 90%-116% with TDM at days 1 and 3. This comprehensive study reinforces the interest of TDM in managing interindividual variability in busulfan exposure. Therapeutic drug monitoring can reliably be implemented from 3 samples using the Bayesian approach, preferably over 2 days. If using the latter is not possible, the formulas developed herein could present an alternative in Thai patients.
Sections du résumé
BACKGROUND
BACKGROUND
Conditioning bifunctional agent, busulfan, is commonly used on children before hematopoietic stem cell transplantation. Currently, at the Ramathibodi hospital, Bangkok, Thailand, initial dosing is calculated according to age and body surface area, and 7 samples per day are used for therapeutic drug monitoring (TDM). This study aimed to identify the best strategies for individual dosages a priori from patient characteristics and a posteriori based on TDM.
METHODS
METHODS
The pharmacokinetic data set consisted of 2018 plasma concentrations measured in 135 Thai (n = 135) pediatric patients (median age = 8 years) and were analyzed using a population approach.
RESULTS
RESULTS
Body weight, presence of malignant disease, and genetic polymorphism of Glutathione S-transferase Alpha-1 (GSTA1) were predictors of clearance. The optimum sampling times for TDM concentration measurements were 0.25, 2, and 5 hours after a 3-hour infusion. This was sufficient to obtain a Bayesian estimate of clearance a posteriori. Simulations showed the poor performance of a priori formula-based dose calculations with 90% of patients demonstrating a 69%-151% exposure interval around the target. This interval shrank to 85%-124% if TDM was carried out only at day 1 and to 90%-116% with TDM at days 1 and 3.
CONCLUSIONS
CONCLUSIONS
This comprehensive study reinforces the interest of TDM in managing interindividual variability in busulfan exposure. Therapeutic drug monitoring can reliably be implemented from 3 samples using the Bayesian approach, preferably over 2 days. If using the latter is not possible, the formulas developed herein could present an alternative in Thai patients.
Identifiants
pubmed: 38758634
doi: 10.1097/FTD.0000000000001225
pii: 00007691-990000000-00226
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Lawson R, Staatz CE, Fraser CJ, et al. Review of the pharmacokinetics and pharmacodynamics of intravenous busulfan in paediatric patients. Clin Pharmacokinet. 2021;60:17–51.
McCune JS, Gooley T, Gibbs JP, et al. Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30:167–173.
Bartelink IH, Lalmohamed A, Van Reij EML, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016;3:e526–e536.
Dix SP, Wingard JR, Mullins RE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. 1996;17:225–230.
Philippe M, Neely M, Rushing T, et al. 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 Transplant. 2019;54:448–457.
Geddes M, Kangarloo SB, Naveed F, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14:220–228.
Center for Drug Evaluation and Research [CDER], US FDA. Clinical Pharmacology and Biopharmaceutics Review(s): Busulfan [Internet]. Silver Springs: US FDA; 2001. [cited 2022 Nov 16]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/20-954S004_Busulfex_BioPharmr.pdf
European Medicines Agency. Busilvex: EPAR—Product Information. Annex I – Summary of Product Characteristics [Internet]. Amsterdam: EMA; 2003. [cited 2019 Jul 23]. Available at: https://www.ema.europa.eu/en/documents/product-information/busilvex-epar-product-information_en.pdf.
Ben Hassine K, Nava T, Théoret Y, et al. Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: results from a multicenter population pharmacokinetic study. CPT Pharmacometrics Syst Pharmacol. 2021;10:1043–1056.
Lawson R, Paterson L, Fraser CJ, et al. Evaluation of two software using Bayesian methods for monitoring exposure and dosing once-daily intravenous busulfan in paediatric patients receiving haematopoietic stem cell transplantation. Cancer Chemother Pharmacol. 2021;88:379–391.
Sandström M, Karlsson MO, Ljungman P, et al. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients. Bone Marrow Transplant. 2001;28:657–664.
de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–864.
Bartelink IH, Bredius RGM, Ververs TT, et al. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:88–98.
Nguyen AH, Biswas M, Puangpetch A, et al. Effect of GSTA1 variants on busulfan-based conditioning regimen prior to allogenic hematopoietic stem-cell transplantation in pediatric Asians. Pharmaceutics. 2022;14:401.
Zwaveling J, den Hartigh J, Lankester AC, et al. Once-daily intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Anticancer Drugs. 2006;17:1099–1105.
Lee JW, Kang HJ, Lee SH, et al. Highly variable pharmacokinetics of once-daily intravenous busulfan when combined with fludarabine in pediatric patients: phase I clinical study for determination of optimal once-daily busulfan dose using pharmacokinetic modeling. Biol Blood Marrow Transplant. 2012;18:944–950.
Poinsignon V, Faivre L, Nguyen L, et al. New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning. Pediatr Blood Cancer. 2020;67:e28603.
Elmokadem A, Riggs MM, Baron KT. Quantitative systems pharmacology and physiologically-based pharmacokinetic modeling with mrgsolve: a hands-on tutorial. CPT Pharmacometrics Syst Pharmacol. 2019;8:883–893.
Le Louedec F, Puisset F, Thomas F, et al. Easy and reliable maximum a posteriori Bayesian estimation of pharmacokinetic parameters with the open-source R package mapbayr. CPT Pharmacometrics Syst Pharmacol. 2021;10:1208–1220.
FelicienLL/BUSULFANAPP [Internet]. GitHub. [cited 2023 Sep 12]. Available at: https://github.com/FelicienLL/BUSULFANAPP
Lawson R, Staatz CE, Fraser CJ, et al. Population pharmacokinetic model for once-daily intravenous busulfan in pediatric subjects describing time-associated clearance. CPT Pharmacometrics Syst Pharmacol. 2022;11:1002–1017.
DeLeve LD, Wang X. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology. 2000;60:143–154.
Almog S, Kurnik D, Shimoni A, et al. Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination. Biol Blood Marrow Transplant. 2011;17:117–123.
ten Brink MH, van Bavel T, Swen JJ, et al. Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics. 2013;14:1683–1690.
Czerwinski M, Gibbs JP, Slattery JT. Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996;24:1015–1019.
Vaughan WP, Carey D, Perry S, et al. A limited sampling strategy for pharmacokinetic directed therapy with intravenous busulfan. Biol Blood Marrow Transplant. 2002;24:1015–1019.
Dupuis LL, Sibbald C, Schechter T, et al. IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies. Biol Blood Marrow Transplant. 2008;14:576–582.
Neely M, Philippe M, Rushing T, et al. Accurately achieving target busulfan exposure in children and adolescents with very limited sampling and the BestDose software. Ther Drug Monit. 2016;38:332–342.
Marsit H, Philippe M, Neely M, et al. Intra-individual pharmacokinetic variability of intravenous busulfan in hematopoietic stem cell-transplanted children. Clin Pharmacokinet. 2020;59:1049–1061.
Alsultan A, Albassam AA, Alturki A, et al. Can first-dose therapeutic drug monitoring predict the steady state area under the blood concentration-time curve of busulfan in pediatric patients undergoing hematopoietic stem cell transplantation? Front Pediatr. 2022;10:834773.
Bognàr T, Kingma JS, Smeijsters EH, et al. Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen. Bone Marrow Transplant. 2023;58:762–768.