Practical Pharmacogenetics and Single Nucleotide Polymorphisms (SNPs) in Renal Transplantation

  • Jose M
  • Boso V
  • Rojas L
  • et al.
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Abstract

1. Introduction Optimizing balance between therapeutic efficacy and the occurrence of adverse events is the main goal of individualized medicine. This takes even more importance in narrow therapeutic index drugs such as immunosuppressants. These drugs are highly effective in preventing acute graft rejection but tacrolimus, cyclosporine and mycophenolic acid show highly variable pharmacokinetics and pharmacodynamics. Still nowadays the fragile equilibrium between the risks and benefits of immunosuppression makes the management of immunosuppressive pharmacotherapy a challenge. Therapeutic drug monitoring (TDM) is an essential and indispensable instrument for calci‐ neurin inhibitors dosing, reducing the pharmacokinetic component of variability by control‐ ling drug blood concentrations. But TDM is only possible once the drug is administered and steady state and patient’s compliance are achieved, so complementary strategies are needed. Moreover, despite correct TDM, it may take several days or even weeks to reach target blood concentrations. For many patients this time periods are not appropriate in order to achieve sufficiently high concentrations to prevent graft rejection or adverse reactions or, on the other hand, without exposing the patient to excessive toxicity. In this sense, Pharmacogenetics is an interesting approach, helpful to manage immunosuppressant drugs. Changes in expression or function of proteins and enzymes involved in drug transport, metabolism or mechanism of action will cause changes in drug’s absorption, metabolism and distribution and, therefore, can lead to changes in the response and toxicity of the treatment. Characterization of these genetic variants, mainly Single Nucleotide Polymorphisms (SNPs), can help to establish effective doses and to minimize adverse effects. Many publications, including our own, have found statistically significant correlations between (SNPs) and tacrolimus and/or cyclosporine dose-corrected blood levels. There are also works correlating certain variants in SNPs with safety and efficacy of the treatment. Even some researchers, working groups and consortia recommend guidelines for initial dosing adjust regarding this SNPs. Pharmacogenetic tests are becoming cheaper every day, so the cost of performing these assays is getting more assumable, especially when clinically relevant complications are demonstrated. The incorporation of pharmacogenetic studies to the real clinical practice will depend on the creation of well-designed sets of SNPs that, in a cost-effectiveness manner, could correlate clinical complications with genotypes, taking into consideration the whole and complicated treatment in polymedicated patients. Many results contribute to highlight the need of prospective controlled studies, with pharmacogenetic analysis prior to transplantation. This will probably be the critical point for the regulatory agen‐ cies to settle the most relevant polymorphisms as validated biomarkers to be widely used in the clinical transplantation setting. For all this reasons, our aim in this chapter is to provide an easy explanation about what a polymorphism is and an updated view of the most relevant SNPs with evidence of their implication in safety and efficacy of immunosuppressive treatment in renal transplantation. The final goal is to give a summary from basic knowledge to concrete examples that help to improve the medical doctors’ knowledge of the clinical impact of Pharmacogenetics in their daily practice.

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APA

Jose, M., Boso, V., Rojas, L., Bea, S., Sanchez, J., Hernandez, J., … F., S. (2013). Practical Pharmacogenetics and Single Nucleotide Polymorphisms (SNPs) in Renal Transplantation. In Current Issues and Future Direction in Kidney Transplantation. InTech. https://doi.org/10.5772/54733

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