Pharmacogenomics: towards personalized medicine Sandra Ballesteros Ribera
Adverse drug reactions Pharmacology industry problems Adverse drug reactions 3-4th cause of mortality in developmental countries 5% of total hospital admissions High costs
Adverse drug reactions Pharmacology industry problems Adverse drug reactions 3-4th cause of mortality in developmental countries 5% of total hospital admissions High costs
Adverse drug reactions Pharmacology industry problems Adverse drug reactions 3-4th cause of mortality in developmental countries 5% of total hospital admissions High costs
Adverse drug reactions Pharmacology industry problems Adverse drug reactions 3-4th cause of mortality in developmental countries 5% of total hospital admissions High costs
The paradox of Modern Drug Development Adverse Drug Reactions Doctors treat individual patients who can vary in its response to drug theraphy. Clinical trials provide evidence of efficacy and safety at usual doses in populations. Effective & safe No response Adverse Drug Reactions "one-dose-fits-all" approach
Differences in response to the treatment are due to… “It is far more important to know what person has the disease than what disease has the person” The disease is heterogeneous and varies. Hippocrates 460 a. C.-370 a. C The individuals are different and vary.
Pharmacogenomics Pharmacogenomics: study of how genes influence drug response. The overall goal is to use the genetic testing to stratify patients to optimize the treatment. Pharmacogenetic profile High risk of ADR or low efficacy of the drug Treat with alternative drug or dose Moderate risk of ADR/ moderate efficacy of the drug Treat with alternative drug or dose Low risk of ADR /high efficacy of the drug Treat with conventional dose All patients with the same diagnosis
Abacavir hypersensitivity Treatment of HIV HLA-B*5701 Predictor of abacavir hypersensitivity syndrome.
Drug-metabolizing enzymes: CYP2D6 metabolizes nearly 25% of clinically used drugs. The most polymorphic gene of the CYT450. Effects on Metabolizer phenotypes: poor, intermediate, extensive and ultra-rapid status rs5758550 and rs133333 in the R1 cluster region were associated with >2-fold increased CYP2D6 transcription.
Genomic biomarkers Pharmacogenetic or pharmacogenomic biomarker: genetic or genomic marker that is associated with drug response. Prognostic biomarker: provides information on the likely course of cancer. Biomarkers in Colorectal tumors High Microsatellite instability favourable prognosis compared to microsatellite stable/low-frequency MSI tumors. predictive of response to immunotherapy agents: nivolumab and pembrolizumab.
promoting cell proliferation and tumour growth Genomic biomarkers Predictive biomarker: identify patients most likely to benefit from treatment and/or those predisposed to toxicity. V600E BRAF mutation in cutaneous metastatic melanoma constitutive activation promoting cell proliferation and tumour growth Vemurafenib
Dabrafenib and Trametinib Genomic biomarkers Predictive biomarker: identify patients most likely to benefit from treatment and/or those predisposed to toxicity. V600E BRAF mutation in cutaneous metastatic melanoma Vemurafenib resistance! Ras and Mek mutations Dabrafenib and Trametinib
The pharmacogenomics is a promising beginning of precision medicine and even personalized medicine, in which drugs and drug combinations are optimized for reduce groups of patients or even for each individual's unique genetic map.
Bibliography Becquemont, L. (2010). HLA: a pharmacogenomics success story. Pharmacogenomics. Vol. 11(3), pp. 277–28. Leslie, J.D. and Joseph, A.W. (2016). Pharmacogenomics in the age of personalized medicine. Elviser. Vol 21-22, pp. 11-16. Patel, J. N. (2016). Cancer pharmacogenomics, challenges in implementation and patient-focuses perspectives. Pharmacogenomics and personalized medicine. Vol. 9, pp. 65-77. Wang, D., Papp, A. C. and Sun, X. (2015). Functional characterization of CYP2D6 enhancer polymorphis. Human Molecular Genetics. Vol. 24(6), pp. 1556–1562.
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