SIRISHA ANNAVARAPU

DEPT OF PHARMACOLOGY, KIMS

Introduction

• Pharmacogenomics deals with the influence of

genetic variation on drug response by co-relating

gene expression or polymorphism with a drug’s

efficacy or toxicity

• It intends to identify individuals who are either more

likely or less likely to respond to a drug, as well as

those who require altered dose of certain drugs

Introduction

• Pharmacogenetics is often a study of the variations

in a targeted gene, or group of functionally related

genes.

• Pharmacogenomics is the use of genetic information

to guide the choice of drug and dose on an individual

basis.

Pharmacogenomics Pharmacogenetics Genetic toxicology

use of geneticinformation to guide the choice of drug and dose on an individual basis.

The study ofgenetic basis forvariability in drugResponse

Study of the effect of chemical or physical agents on the heredity material (DNA) and on the genetic process of living cells.

Differences

NORMAL GENE SNP VARIANT GENE

TODAY’S DRUG

PHARMACOGENOMIC DRUG

Principle of Pharmacogenomics

Potential of Pharmacogenomics

GENETICS AND MUTATION

Genotype• The genetic constitution of an individual.

Experimental evaluation of Genotype (Genotyping)

Collect blood (> 1 ml)

Isolate DNA from nucleated blood cells.

Amplify number of copies of DNA by the Polymerase

Chain Reaction (PCR).

Genotype by sequencing or probing.

Genetic polymorphism / mutation

• Mutations are inheritable changes produced in the

genetic information stored in the DNA of living cells.

Mutation is a difference in DNA sequence among

individuals, groups, or populations. Sources include

SNPs, sequence repeats, insertions, deletions and

recombination.

Single Nucleotide Polymorphism

(SNP)

• DNA sequence variation that occurs when a single

nucleotide in the genome sequence is altered.

…CTAGATACGAACTGCATC…

…CTAGATACGGACTGCATC…

Consequences of polymorphisms

• May result in a different amino acid or stop

codon

• May result in a change in protein function or

quantity

• No effect

ADVANTAGES AND

DISADVANTAGES OF

PHARMACOGENOMICS

Advantages of pharmacogenomics

Barriers of pharmacogenomics

1. Complexity of finding gene variations that affect drug

response.

Millions of SNPs must be identified and analyzed to

determine their involvement (if any) in drug response.

Many genes are likely to influence responses

Limited knowledge of which genes are involved with

each drug response

Confidentiality, privacy and the use and storage of

genetic information

Barriers of pharmacogenomics

2. Educating healthcare providers & patients

• Complicates the process of prescribing and

dispensing drugs

• Physicians must execute an extra diagnostic step to

determine which drug is best suited to each patient

• Need for a better understanding of genetics by all

physicians

Barriers of pharmacogenomics

3. Disincentives for drug companies to make multiple

pharmacogenomic products

Most pharmaceutical companies have been successful

with their "one size fits all" approach to drug

development

For small market- Pharmaceutical companies has to

spend hundreds of millions of dollars on

pharmacogenomics based drug development

Amphichip

• Determine the genotype of the patient in terms of two

CYPP450 enzymes: 2D6 and 2C19

• FDA approved the test on December 24, 2004. The

AmphiChip CYP450 test is the first FDA

approved pharmacogenetic test.

PHARMACOGENOMICS IN

DRUG METABOLISM

Role of genes in PK & PD

Candidate genes for variable drug

response(1) Proteins involved in drug transport:

Drug transporters (e.g. ABC and SLC) show

considerable genetic variation including many

functional polymorphisms.

(2) Genes that code for drug-metabolizing enzymes

(DME): Most DME-encoding genes have

polymorphisms that have been shown to influence

enzymatic activity.

Pharmacogenomics of drug

transporters

• PGP (MDR 1) serves as barrier against entry of

compounds into the body, as well as from entering

tissues

OATP-C*5 and OATP-C*9 have reduced uptake of OATP-C substrates

High plasma levels of pravastatin

Increased toxicity and reduced efficacy

Enzymes involved in drug

metabolism

Effects of CYP variants on

therapeutic efficacy

Examples of Genetic Polymorphisms

Influencing Drug Response GENE PRODUCT (GENE) RESPONSES AFFECTED

CYP2C9 Anticoagulant effect of

warfarin

CYP2C19 Peptic ulcer response to

omeprazole

CYP2D6 Tardive dyskinesia from

antipsychotics, narcotic side

effects, codeine efficacy,

imipramine dose requirement,

β blocker effect

CYP2D6

CYP 2C

• CYP2C9 * 2 and CYP2C9 * 3 variants are of

significance- PM

Drugs whose safety and efficacy

are affected by gene variations

Using pharmacogenomics to predict

and prevent adverse drug reactions • Abacavir:

• Patients who carry the HLA-B*5701 allele are at high

risk for experiencing a hypersensitivity reaction to

abacavir.

• Prior to initiating therapy with abacavir, screening for

the HLA-B*5701 allele is recommended; this

approach has been found to decrease the risk of a

hypersensitivity reaction.

• Irinotican: Patients homozygous or heterozygous for

the UGT1A1*28 allele have elevated levels of SN-38

and consequently are susceptible to bone marrow and

gastrointestinal side effects

Using pharmacogenomics to

predict effectiveness

• Clopidogrel:

• CYP2C19, mediates the conversion of clopidogrel

into the active metabolite. Patients who carry

variations in CYP2C19 are considered poor

metabolizers and show reduced ability to convert

clopidogrel into its active metabolite, resulting in a

diminished antiplatelet effect.

• Tamoxifen:

• ER+ breast cancer

• CYP2D6*4 --- Poor metabolizer(7-10%)- frequent

relapse , worse disease free survival

Using pharmacogenomics to

predict optimal dose

• Warfarin:

• Warfarin has a narrow therapeutic index; variations in

CYP2C9 and VKORC1, make it difficult to predict

the effective dose. Those carrying certain CYP2C9

and VKORC1 variations are likely to require altered

doses and may require prolonged time to reach a

stable maintenance dose.

Targets and receptors

Angiotensin-converting

enzyme (ACE)

ACE inhibitors (e.g.,

enalapril)

Renoprotective effects,

hypotension, left

ventricular mass

reduction, cough

Thymidylate synthase Methotrexate Leukemia response,

colorectal cancer

response

β2 Adrenergic receptor β2 Antagonists (e.g.,

albuterol, terbutaline)

Bronchodilation,

Dopamine receptors Antipsychotics Antipsychotic

response (D2, D3, D4),

tardive dyskinesia

PHARMACOGENOMICS IN

CLINICAL TRIALS

Applying PGs

.

DISEASE GENETICS

TARGETVARIABILITY

SELECTINGRESPONDERS

PHARMACO-GENETICS

Discovery Development

Choosing

the Best

Targets

Better

Understandin

g of our

Targets

Improving

Early

Decision

Making

Predicting

Efficacy

and Safety

Pharmacogenomics in various stages

of drug development• Drug target identification –identification and

characterization of gene coding for the drug target

and to assess the variability.

• Phase I II &III – patient selection, inclusion and

exclusion criteria, dose range selection, dose

modification ,interpretation of trial result based on

Pharmacogenetic test results.

• Phase IV analysis of reported adverse effects with

pharmacogenetic tests.

References • Ellis KJ, Stouffer GA, McLeod HL, Lee CR.

Clopidogrel pharmacogenomics and risk of

inadequate platelet inhibition: U.S. FDA

recommendations. (2009). Pharmacogenomics

10(11):1799–1817.

• Collins FS. 2010. The Future of Personalized

Medicine. NIH Medline Plus 5(1):2–3.

• Belle DJ, Singh H. (2008). Genetic Factors in Drug

Metabolism. Am Fam Physician 77(11):1553–1560.

• Rollason V, Samer C, Piguet V, Dayer P, Desmeules

J. (2008). Pharmacogenomics of analgesics: Toward

the individualization or prescription.

Pharmacogenomics 9(7):905–933.

• Mallal S, Phillips E, Carosi G, Molina JM, Workman

C, Tomazic J et al. (2008). HLA-B*5701 screening

for hypersensitivity to abacavir. N Engl J Med

358(6):568–579.

• Willmann S, Edginton AN, Coboeken K, Ahr A,

Lippert J. (2009). Risk to the Breast-Fed

NeonateFrom Codeine Treatment to the Mother: A

Quantitative Mechanistic Modeling Study. Clin

Pharmacol Ther 86(6):634–643.

• Ingelman-Sundberg M, Sim SC, Gomez

A,Rodriguez-Antona C. (2007). Influence of

cytochrome P450 polymorphisms on drug

therapies:Pharmacogeneic, pharmacoepigenetic, and

clinical aspects. Clin Pharmacol Ther 116:496–526.

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