PHARMACOGENOMICS

Cristina Miracle Huguet 11.12.2017

1. Drug response variability

2. Origens of pharmacogenomics

3. Pharmacogenomics studies and applications

4. Clinical implementation

5. Critical issues

6. Resources and databases

7. Future directions

8. Literature

SUMMARY

DRUG RESPONSE VARIABILITY

of hospitalized patients

experience adverse

drug reactions

of hospital admissions

are related to adverse

drug reactions

Adverse drug reactions

are the 4th leading

cause of death in USA

One-size-fits-all approach:

http://safety-code.org/providers/#

DRUG RESPONSE VARIABILITY

of hospitalized patients

experience adverse

drug reactions

of hospital admissions

are related to adverse

drug reactions

Adverse drug reactions

are the 4th leading

cause of death in USA

One-size-fits-all approach:

http://safety-code.org/providers/#

Age

Sex

Comorbidities

Life

style Environmental

Race Genetics

Pharmacogenetics: studies how

genetic differences in individual

candidate genes contribute to the

observed variablity in drug response.

Pharmacogenomics: studies

how multiple genes (DNA

variation + RNA expression)

impact drug response.

“The influence of inheritance

in drug response”

Friedrich Vogel, 1959

Fatal hemolytic anemia

Pythagoras, 510 BC

First polymorphic human

drug methabolizing gene

CYP2D6, 1987

ORIGINS

PHARMACOGENOMIC STUDIES

DISCOVERY APPROACHES

Candidate gene approach

Genome wide association approach

Hybrid approach

Absorption

PHARMACOKINETICS PHARMACODYNAMICS

Excretion

Distribution

Metabolism Receptors Enzymes

Ion

channels

Immune

System

• Hypotesis driven • Metabolic enzymes

• Discovery driven • Microarray technologies

• Custom SNP chips for important variants

CYP2D6 - Codeine ALOX5 – Lipoxygenase inhibitors

PHARMACOGENOMICS APPLICATIONS

Identification of patients at risk of adverse reactions

Selection of patients molt likely to benefit from treatment

Establish rational safe and effective use of treatment dosing

Inform of clinical trial design and drug development

Serious Adverse Drug Reactions: type A and type B

Agents with narrow terapeutic window

Severe drug toxicity consequences

Potentially fatal lack of efficacy consequences

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., &

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ang,

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CLINICAL IMPLEMENTATION

Risks as a result of testing

Improved health outcomes

?

Clinical Utility Clinical Pharmacogenomics

Implementation Consortium

https://www.pharmgkb.org/page/clinAnnLevels

CLINICAL GUIDELINES

CLINICAL IMPLEMENTATION

Risks as a result of testing

Improved health outcomes

?

Clinical Utility

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Clinical Pharmacogenomics

Implementation Consortium

https://www.pharmgkb.org/page/clinAnnLevels

CLINICAL GUIDELINES

CRITICAL ISSUES

Pharmacogenomics is unlikely to be useful for

improving prescribing for the majority of drugs

17

18.000 human genes

Considered actionable

for pharmacogenomics

Rel

ling,

M. V

, & E

van

s, W

. E. (

20

16

).

Ph

arm

aco

gen

om

ics

in t

he

Clin

ic Pharmacogenomic science:

involvement of multiple gene

products

Translational incentives:

research funding, academic

centres, pharmaceutic indstry,

drug regulatory agencies…

Healthcare professional

education in clinical genomics

sience

Patients acceptance: informed

patients and realistic expectations

RESOURCES AND DATABASES

RESOURCES AND DATABASES

RESOURCES AND DATABASES

FUTURE DIRECTIONS

“There is a growing body of evidence that pharmacogenomics will

be an expanding component of evidence-based precision medicine.”

“Overall steady progress is being made toward pervasive application

of pharmacogenomics testing.”

“Many challenges remain, including keeping up with the complex

regulatory landscape, new sequencing technologies and approved

devices, translating research successes to clinical successes and

discovering new markers.”

“… pharmacogenomics shows tremendous promise to significantly

improve the safety and effectivenes of medications in the future.”

LITERATURE

1. Relling, M. V, & Evans, W. E. (2016). Pharmacogenomics in the Clinic, Nature, 526(7573), 343–350. http://doi.org/10.1038/nature15817

2. Mooney, S. D. (2016). Progress Towars the Integration of Pharmacogenomics in Practice, Hum Genet, 134(5), 459–465. http://doi.org/10.1007/s00439-014-1484-7

3. Lee, J. W., Aminkeng, F., Bhavsar, A. P., Shaw, K., & Carleton, B. C. (2014). The emerging era of pharmacogenomics : current successes , future potential , and challenges, 21–28. http://doi.org/10.1111/cge.12392

4. Charlab, R., & Zhang, L. (2013). Chapter 1 Pharmacogenomics : Historical Perspective and Current Status, 1015. http://doi.org/10.1007/978-1-62703-435-7

5. Weinshilboum, R., & Wang, L. (2004). Pharmacogenomics: Bench to Bedside, Nature Reviews, 3(September). https://doi.org/10.1038/nrd1497

PHARMACOGENOMICS

Cristina Miracle Huguet 11.12.2017