The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant RecipientsReportar como inadecuado




The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant Recipients - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Drugs in RandD

, Volume 17, Issue 2, pp 279–286

First Online: 22 February 2017DOI: 10.1007-s40268-017-0177-9

Cite this article as: Madsen, M.J., Bergmann, T.K., Brøsen, K. et al. Drugs R D 2017 17: 279. doi:10.1007-s40268-017-0177-9

Abstract

IntroductionTacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 CYP 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations. Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A5*3, PPARA c.209-1003G>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free >85% population of Danish pediatric and adult kidney transplant recipients.

MethodsSeventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients’ medical charts.

ResultsIt was confirmed that CYP3A5*1 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations compared with noncarriers. Adults had 56 and 77% lower trough concentrations at 6 weeks p = 0.0003 and 1 year, respectively p < 0.0017, and, similarly, children had 65 and 39% lower median concentrations, with p values of 0.006 and 0.011, respectively. No association was found for PPARA c.209-1003G>A, POR*28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus CMV within the first year was identified p < 0.05. Only 29% of trough concentrations measured between 2 and 12 weeks post-transplantation were on target.

ConclusionThis study shows that the known association of the CYP3A5 genotype with tacrolimus dose-adjusted trough concentrations has the same impact in a corticosteroid-sparse population. The association between PPARA variance and infections with CMV will need further investigation.

Mads Juul Madsen and Troels K. Bergmann contributed equally to the writing of this article.

Electronic supplementary materialThe online version of this article doi:10.1007-s40268-017-0177-9 contains supplementary material, which is available to authorized users.





Autor: Mads Juul Madsen - Troels K. Bergmann - Kim Brøsen - Helle Charlotte Thiesson

Fuente: https://link.springer.com/







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