GSTA1 Genetic Variants and Conditioning Regimen: Missing Key Factors in Dosing Guidelines of Busulfan in Pediatric Hematopoietic Stem Cell Transplantation

• Published in: Biology of blood and marrow transplantation Vol. 23; no. 11; pp. 1918 - 1924
• Main Authors: Nava, Tiago, Rezgui, Mohamed A., Uppugunduri, Chakradhara R.S., Curtis, Patricia Huezo-Diaz, Théoret, Yves, Duval, Michel, Daudt, Liane E., Ansari, Marc, Krajinovic, Maja, Bittencourt, Henrique
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2017
• Subjects: Busulfan; Busulfan - pharmacokinetics; Busulfan - therapeutic use; Child, Preschool; Children; Dosing guidelines; Female; Genetic Variation - genetics; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; GSTA1; Hematopoietic Stem Cell Transplantation - methods; Humans; Infant; Male; Pharmacogenetics; Pharmacokinetics; Transplantation Conditioning - methods; Pharmacogenetics; Busulfan; Children; Dosing guidelines; Pharmacokinetics; GSTA1
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2017.07.022

•The methods currently used to calculate busulfan dose are influenced by the GSTA1 genotype.•GSTA1 genotypes influence is best expressed by grouped diplotypes according their potential expression capacity.•The incorporation of GSTA1 haplotypes as a covariate in a population pharmacokinetics model is suggested to improve dose prediction. Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose.