1. Pharmacogenomics: towards personalized medicine
Sandra Ballesteros Ribera

2. Adverse drug reactions
Pharmacology industry problems
Adverse drug reactions
3-4th cause of mortality in developmental countries
5% of total hospital admissions
High costs

3. Adverse drug reactions
Pharmacology industry problems
Adverse drug reactions
3-4th cause of mortality in developmental countries
5% of total hospital admissions
High costs

4. Adverse drug reactions
Pharmacology industry problems
Adverse drug reactions
3-4th cause of mortality in developmental countries
5% of total hospital admissions
High costs

5. Adverse drug reactions
Pharmacology industry problems
Adverse drug reactions
3-4th cause of mortality in developmental countries
5% of total hospital admissions
High costs

6. 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

7. 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.

8. 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

9. Abacavir hypersensitivity
Treatment of HIV
HLA-B*5701
Predictor of abacavir hypersensitivity syndrome.

10. 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
rs and rs in the R1 cluster region were associated with >2-fold increased CYP2D6 transcription.

11. 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.

12. 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

13. 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

14. 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.

15. 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
Patel, J. N. (2016). Cancer pharmacogenomics, challenges in implementation and patient-focuses perspectives. Pharmacogenomics and personalized medicine. Vol. 9, pp
Wang, D., Papp, A. C. and Sun, X. (2015). Functional characterization of CYP2D6 enhancer polymorphis. Human Molecular Genetics. Vol. 24(6), pp. 1556–1562.

16. Thanks for your attention