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Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes

Abstract

β-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 μg ml−1 and 360 μg ml−1 h−1, respectively; nonresponse AUC limit of 250 μg ml−1 h−1). Ninety-nine β-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors.

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Acknowledgements

We thank CoQuaLab (www.coqualab.it) for its methodological support and assistance in the preparation and execution of the pharmacogenetic analysis. Laboratory of Clinical Pharmacology and Pharmacogenetics: UNI EN ISO UNI EN ISO 9001:2008 and 13485:2012 (CE-IVD) Certified Laboratory; Certificate No. IT-64386; Certification for: ‘DESIGN, DEVELOPMENT AND APPLICATION OF DETERMINATION METHODS FOR ANTI-INFECTIVE DRUGS. PHARMACOGENETIC ANALYSES.’

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Allegra, S., Cusato, J., De Francia, S. et al. Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes. Pharmacogenomics J 18, 506–515 (2018). https://doi.org/10.1038/tpj.2017.43

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