PHARMACOGENOMICS Master in Advanced Genetics Genomics Carmen Mara

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PHARMACOGENOMICS Master in Advanced Genetics Genomics Carmen María Armada Sánchez

PHARMACOGENOMICS Master in Advanced Genetics Genomics Carmen María Armada Sánchez

TRADITIONAL MEDICINE “ONE-SIZE -FITS-ALL” PERSONALIZED MEDICINE Responds to normal dose Responds to lower dose

TRADITIONAL MEDICINE “ONE-SIZE -FITS-ALL” PERSONALIZED MEDICINE Responds to normal dose Responds to lower dose Response s to higher dose adverse success no effects Responses to alternative medication ↓ TOXICITY ↑EFFICACY

10, 1 % • of hospitalized patients experience adverse drug reaction 3, 5% •

10, 1 % • of hospitalized patients experience adverse drug reaction 3, 5% • of hospital admissions are related to adverse drug reactions 4 th • Adverse drug reactions is the 4 th leading cause of death in the USA

BASIC CONCEPTS Pharmacogenetics (1 gen 1 drug) • Studies the effect of genetic variation

BASIC CONCEPTS Pharmacogenetics (1 gen 1 drug) • Studies the effect of genetic variation in individuals on their response to drugs Pharmacogenomics (Genoma drugs) • Identifies genoma variants from candidate genes related to drug effects • Pharmacokinetics (A, D, M, E) and Pharmacodynamics (drug action) Pharmacogene: every gene that plays a role in drugs response Drug class Drugs Examples of adverse reactions Antidepressants Clomipramine, Citalopram Cardiotoxicity, therapy failure Analgesics Codeine Respiratory depression, ↓pain relief Thiopurines Azathioprine, Mercaptopurine Myelosuppresion

History Pythagoras 510 BC People reacting differently to the ingest of fava beans Human

History Pythagoras 510 BC People reacting differently to the ingest of fava beans Human Genome Project, 2001 “Pharmacogenom ics” Friedrich Vogel 1959 “Pharmacogeneti cs”, studies in twins CYP 2 D 6, 1987 First polymorphic human drug metabolizing gene

Projects that helped to develop Pharmacogenomics

Projects that helped to develop Pharmacogenomics

Genome-Wide Association Studies: discover new variants

Genome-Wide Association Studies: discover new variants

Gene Expression Tests: Breast Cancer • 70 genes • Low/high risk

Gene Expression Tests: Breast Cancer • 70 genes • Low/high risk

Pharmacogenomics in your pocket Drug substances with essential therapy modifications recommended What is it?

Pharmacogenomics in your pocket Drug substances with essential therapy modifications recommended What is it? The Medication Safety Code represents a patient-specific genetic profile regarding important pharmacogenes. How does it work? Scaning the QR code, you are led to a website that displays patientspecific drug dosing recommendations.

Pharmacogenomics is unlikely to be useful for improving prescribing for the majority of drugs

Pharmacogenomics is unlikely to be useful for improving prescribing for the majority of drugs 120 0 • Individual molecular entities approved as drugs 15% • Pharmacogenomic information in the label 7% • Actionable (level A/B) Table with drugs aproved by the US FDA with genetic indications DRUG INDICATION GENE(s) Cetuximab EGFR+/KRAS- metastatic colorectal cancer EGFR and KRAS Ivacaftor Cystic Fibrosis with G 551 D mutation in CFTR

DATABASES AND RESOURCES: PHARMGKB Aggregation, curation, integration and dissemination of knowlegde regarding the impact

DATABASES AND RESOURCES: PHARMGKB Aggregation, curation, integration and dissemination of knowlegde regarding the impact of human genoma variation on drug response

DATABASES AND RESOURCES: PGRN Their mission is to catalyse and lead research in precision

DATABASES AND RESOURCES: PGRN Their mission is to catalyse and lead research in precision medicine for the discovery and translation of genomics variation influencing therapeutic and adverse drug effects

DATABASES AND RESOURCES: CPIC Facilitate use of pharmacogenetic tests for patient care: • BARRIER:

DATABASES AND RESOURCES: CPIC Facilitate use of pharmacogenetic tests for patient care: • BARRIER: difficulty of translating genetic laboratory results into actionable prescribing decisions • GOAL: implementation of pharmacogenetic tests into clinical practice by creating, curating and posting free avaliable, reviewed, evidence-based, updatable and detailed GENE/DRUG guidelines

GUIDELINES CPIC LEVEL PHARMGKB LEVEL PGX ON FDA LABEL Designed to help clinicians understand

GUIDELINES CPIC LEVEL PHARMGKB LEVEL PGX ON FDA LABEL Designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy A/B/C/D: genetic-based prescription action recommended, effective and safe alternative dosing or therapies, … EVIDENCE: 1 a/b: high 2 a/b: moderate 3: low 4: preliminary US Food and Drug Administration • Testing required • Testing recommended • Actionable PGx • Informative PGx Warfarin guideline: https: //cpicpgx. org/content/guideline/publication/warfarin/2017/28198005. pdf

Pharmacogenomic tests to the clinic Gene/dru g choice Clinical guideline (i. e. CPIC) Definitions

Pharmacogenomic tests to the clinic Gene/dru g choice Clinical guideline (i. e. CPIC) Definitions of variants alleles Phenotype assigments Diplotype interactions Assigning dyplotypes Phenotype interactions Building CDS for high risk drugs and phenotypes Harmonizing with existing policies of drug/disease TDM Evaluation of the clinical impact of the implementation Institutional approval of the prescribing recommendation s and policies Pt and clinicial education

FUTURE PROSPECTIVES Challenging to implement the already reported biomarkers to calalog the additional novel

FUTURE PROSPECTIVES Challenging to implement the already reported biomarkers to calalog the additional novel variants Affordable personal genomes: improve diagnostic, prognostic and predictive biomarkers Trial-error procedure patient’s genetic profile Indicate correct drug from the beginning: ↓ hospitalizations Strong evidence that pharmacogenomics will be an expanding component of evidence-based precision

REFERENCES Relling, M. V and Evans, W. E. (2015). Pharmacogenomics in the clinic. Nature.

REFERENCES Relling, M. V and Evans, W. E. (2015). Pharmacogenomics in the clinic. Nature. 526, 343– 350 Carr, D. C. , lfiveric A. and Pirmohamed, M. (2014). Pharmacogenomics: Current State-of-the-Art. Genes. 5(2), 430 -443 Mooney, S. D. (2016). Progress Towards the Integration of Pharmacogenomics in Practice. Hum Genet. 134(5), 459– 465 WEBS: https: //www. pgrn. org/ https: //cpicpgx. org/ https: //www. pharmgkb. org/

THANK YOU FOR YOUR ATTENTION QUESTIONS

THANK YOU FOR YOUR ATTENTION QUESTIONS