La farmacogenética como herramienta de la medicina personalizada: desarrollo de estrategias para su implementación en la práctica clínica e identificación de nuevas asociaciones

Zusammenfassung

Pharmacogenetics (PGx) constitutes an essential tool for personalized medicine. It minimizes Adverse Drug Reactions (RAM) and maximizes treatment efficacy; and ultimately optimizes treatment selection for each patient. The first goal of this doctoral thesis was the development of a strategy for the implementation of PGx in the clinical routine of a third-level care hospital of the Spanish National Health Service. This strategy was based on a SNP-array platform allowing simultaneous genotyping of 180 SNPs related to drug response. During this period (2013-2018) we have performed 3532 PGx tests for different drugs and diseases in the clinical routine of our center. We have also evaluated the utility of a multidisciplinary protocol for the implementation of preemptive genotyping of CYP2C19 in a cohort of haematological patients, defined as risk population for treatment or prophylaxis with Voriconazole. This strategy resulted in a significant increase in the percentage of patients achieving Voriconazole goal therapeutic range and reduced the time window required to achieve it, and therefore improved treatment success. The last aim of this work was the identification of new PGx associations that improved the existing monogenic algorithms for Tacrolimus and Voriconazole treatment optimization, by the incorporation of new biomarkers related to their PGx interindividual variability. During this doctoral thesis we propose new biomarkers, not previously included in clinical prediction algorithms that may be of interest for treatment individualization with these drugs in the clinical practice. In summary, we have developed a strategy that allowed the implementation of PGx in the clinical routine of our center. In addition, we have demonstrated the clinical utility of a preemptive genotyping protocol in a cohort of haematological patients before allogenic hematopoietic cell transplantation defined as a risk population for treatment or prophylaxis with Voriconazole. Finally, we here propose two polygenic predictive models of the pharmacokinetic profile of Tacrolimus and Voriconazole that seem to improve the existing monogenic predictive algorithms.