Pharmacogenetics

Dr. Prashant ShuklaJunior ResidentDept of Pharmacology

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Contents

Background & IntroductionImportance & Goals of

PharmacogenomicsPharmacogenetic phenotypes

Pharmacogenomic testsPharmacogenetics & Drug

developmentPharmacogenetics in clinical practice

Advantages and barriers of pharmacogenomics

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Background

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Types of Genetic VariantsA polymorphism is a variation in the DNA

sequence that is present at an allele frequency of 1% or greater in a population.

Two major types of sequence variation are: ◦single nucleotide polymorphisms (SNPs)◦ insertions/deletions (indels).

Indels are much less frequent in the genome and are of low frequency in coding regions

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SNPs

A single nucleotide polymorphism (SNP), is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population (e.g. >1%).

75%

23%

2%

*

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SNPs types

SNPs usually occur in non-coding regions more frequently than in coding regions. Non-coding SNPs in promoters/enhancers or in 5′ and 3′ untranslated regions may affect gene transcription or transcript stability

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How does genetic variation affect drug effect?

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IntroductionPHARMACOGENETICS: The effect of

genetic variation on drug response, including disposition (PK), safety, tolerability and efficacy (PD).

PHARMACOGENOMICS: It employs the tools for surveying the entire genome to assess multigenic determinants of drug response.

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Pharmacogenetics Pharmacogenomics

The study of genetic basis for variability in drug response

Use of genetic information to guide the choice of drug and dose on an individual basis

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Importance of Pharmacogenetics

“One-size-fits-all drugs” only work for about 60 % of the population at best 

40 % of the population have increased risks of ADR because their genes do not do what is intended of them

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Goals of Pharmacogenetics

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Pharmacogenetic phenotypesGenetic variations which affects the drug

response can be divided in 3 categories:

1. Variations affecting Pharmacokinetics .

2. Variations affecting Drug receptor/target.

3. Disease modifying Variations.

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CYP450sTransferas

es

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Variations affecting PKPhenotypic consequences of

the deficient CYP2D6 phenotype include ◦ increased risk of toxicity of

antidepressants or antipsychotics (catabolized by the enzyme)

◦ lack of analgesic effect of codeine (anabolized by the enzyme)

The ultra-rapid phenotype is associated with extremely rapid clearance and thus decreased efficacy of antidepressants.

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CYP2D6Debrisoquin- Sparteine oxidation

type of polymorphism:1. AR2. CYP2D6 dependent oxidation of

debrisoquin and other drugs impaired3.

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CYP2C19ARAromatic hydroxylation of anticonvulsant

mephenytoinNormal “extensive metabolizers”

( S )- mephenytoin is extensively hydroxylated by CYP2C19 before its glucuronidation and rapid excretion in the urine, whereas ( R )-mephenytoin is slowly N -demethylated to nirvanol, an active metabolite

Poor metabolizers

1. Lack of stereospecific ( S )-mephenytoin hydroxylase activity, so both ( S )- and ( R )-mephenytoin enantiomers are N -demethylated to nirvanol, which accumulates in much higher concentrations.

2. Increase the therapeutic efficacy of omeprazole in gastric ulcer and gastroesophageal reflux diseases.

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CYP2C9

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Relative contributions of different phase II pathways

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Variations affecting PK

Suxamethonium and Pseudocholinesterase deficiency

Genes affecting NAT2

Polymorphism of the TPMT (thiopurine

S-methyltransferase) gene

UGT polymorphism

•Due to mutation, there is formation of abnormal cholinesterase. •The individuals fail to inactivate Suxamethonium rapidly and experience prolonged neuro- muscular blockade.•Frequency: 1/3000

•Rate of drug acetylation varied in different population as a result of balanced polymorphism.•Acetylation by N acetyltransferase (NAT 2) enzyme •Slow acetylators: peripheral neuropathy•Fast acetylators: Hepatotoxicity (wrt Isoniazid)

•AR trait •Rapidly degraded mutant enzyme and consequentlydeficient S -methylation of6-MP, thioguanine, and azathioprine, required fortheir detoxification. •High risk of thiopurine drug-induced fatal hematopoietic toxicity.

•Toxic side effects due to impaired drug conjugation and/or elimination (eg, the anticancer drug irinotecan)

Pharmacogenetics and drug receptor targets

Inactivation of MTHFR

Serotonin receptor polymorphism

Beta receptor polymorphism

Polymorphism in HMG-CoA reductase

Polymorphism in Ion channels

Polymorphism in ACE

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GI toxicity in case of Methotrexate

Responsiveness to Depression

Responsiveness to Asthma

Degree of lipid lowering following

Statins

Cardiac arrhythmias

Renal Function Test

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Polymorphism- modifying diseases

MTHFR polymorphism is linked to homocysteinemia, which in turn affects thrombosis risk. These polymorphisms do not directly affect the PK or PD of prothrombotic drugs, such as glucocorticoids, estrogens, and asparaginase, but may modify the risk of the phenotypic event (thrombosis) in the presence of the drug.

Polymorphisms in ion channels (e.g., HERG, KvLQT1, Mink, and MiRP1) increase the risk of cardiac arrhythmias, which may be accentuated in the presence of a drug that can prolong the QT interval (e.g., macrolide antibiotics, antihistamines).

Clinically available Pharmacogenomic tests

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A pharmacogenetic trait is any measurable or discernible trait associated with a drug, including enzyme activity, drug or metabolite levels in plasma or urine, effects on BP or lipid levels, and drug-induced gene expression patterns

METHODOLOGY

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deCode Genetics, Navigenics, 23andMe

WBCs/ Buccal cells

*PharmGKB

1. HLA gene tests a) ABACAVIR & HLAB*5701 b) ANTICONVULSANTS & HLAB*1502 c) CLOZAPINE & HLA-DQ 1*0201

2. Drug metabolism related gene test a) THIOPURINE & TPMT b) 5-FLUOROURACIL (5-FU) & DPYD c) TAMOXIFEN & CYP2D6 d) IRINOTECAN & UGT1A1*28

Various type of test are

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3) Drug target related gene test a) Trastuzumab & HER 2 b) DASATINIB, IMATINIB & BCR-ABL 1

4) Combined (metabolism & target) gene test

a) WARFARIN & CYP2C9 + VKORC 1 GENOTYPING

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Amplichip

•Determine the genotype of the patient in terms of two CYP450 enzymes: 2D6 and 2C19

•FDA approved the test on Dec 24, 2004. The Amplichip CYP450 test is the first FDA approved pharmacogenetic test.

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Pharmacogenetics & Drug development

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Key players

Role of pharmacogenetics in drug development

1. Can indentify new targets. For eg. a) Genome wide assessment could identify genes whose expression differentiate inflammatory process.

b) A compound could be identified that can change expression of gene responsible for inflammatory process.

c) That compound can serve as starting point

for anti inflammatory drug development. 30

2) Pharmacogenetics may identify subsets of patients who will have a very high or a very low likelihood of responding to an agent.

a) So drug can be tested on selected patients

will respond & low possibility of ADRs. b) This will reduce the time & cost of drug

development.

3) Pharmacogenomics can identify the subset of

patient with higher risk of serious adverse effect.

So these patients can be avoided in trials 31

• Pharmacogenetic data can be submitted to FDA during IND & NDA application.

• If pharmacogenetics studies on animals are available then pharmacogenetic tests should be included in clinical trials.

• During NDA application sponsor should submit the pharmacogenetic data voluntarily, intended to put on label of the drug.

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• Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families (e.g., GPCRs, nuclear receptors, kinases, proteases, etc.) with the ultimate goal of identification of novel drugs and drug targets.

Chemogenomics

Pharmacogenetics in clinical practice

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• Three major types of evidence that should accumulate to implicate polymorphism in clinical care.

1. Screens of tissues from individuals linking the polymorphism to a trait.

2. Complementary preclinical studies.

3. Multiple supportive clinical phenotype/genotype association studies.

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• Despite considerable research activity, pharmacogenetics are not yet widely utilized in clinical practice.

• Dose adjustment on the basis of renal or hepatic dysfunction can be accepted by clinician.

• But there is much more hesitation from clinician to adjust the dose on pharmacogenetic ground.

• This can be due to resistance to accept or can be due to unfamiliarity with the principles of genetics.

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• Another hurdle in the path of Pharmacogenetics is Genetic Discrimination.

• Genetic discrimination occurs if people are treated unfairly because of differences in their DNA that increase their chances of getting a certain disease.

• For example, a health insurer might refuse to give coverage to a woman who has a DNA difference that raises her odds of getting breast cancer .

• Employers also could use DNA information to decide whether to hire or fire workers.

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Genetic Information Non-discrimination Act (GINA) 2008

It is a new federal law that protects Americans from being treated unfairly because of differences in their DNA that may affect their health.

The new law prevents discrimination from health insurers and employers.

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Advantages of pharmacogenomics

To predict a patient’s response to drugsTo develop “customized” prescriptionsTo minimize or eliminate adverse eventsTo improve efficacy and patient

complianceTo improve rational drug developmentPharmacogenetic test need only be

conducted once during the life time.

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Advantages of pharmacogenomics…

To improve the accuracy of determining appropriate dosage of drugs

To screen and monitor certain diseases

To develop more powerful, safer vaccines

To allow improvements in drug discovery and development

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Barriers of Pharmacogenomics1. Complexity of finding gene

variations that affect drug response.

Millions of SNPs must be identified and analyzed to determine their involvement in drug response

2. Confidentiality, privacy and the use and storage of genetic information

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Barriers of Pharmacogenomics...3. Educating healthcare providers

and patientsComplicates the process of

prescribing and dispensing drugsPhysicians must execute an extra

diagnostic step to determine which drug is best suited to each patient

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Barriers of Pharmacogenomics..

4. 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 hundreds of millions of dollars on pharmacogenomic based drug development.

• Pharmacogenomics is in early stages of development.

• Much of the excitement regarding the promise of human genomics hopes on the “PERSONALIZED MEDICINE OR MAGIC BULLETS”.

• Reality of the added complexity of additional testing & need for interpretation of results to individualized dosing has been ignored.

Pharmacogenomics & Personalized medicine

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ClinomicsClinomics is the study of

genomics data along with its associated clinical data.

As personalized medicine advances, clinomics will be a bridge between basic biological data and its effect on human health.

• Pharmacogenomics has great potential to optimize drug therapy.

• Newer molecular diagnostic test will have to be develop to detect polymorphisms.

• Pharmacotherapeutics decisions will soon become fundamental for diagnosing the illness & guiding the choice & dosage of medications.

CONCLUSION

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Scope of Pharmacogenomics

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References[1]Relling MV, Giacomini KM. Pharmacogenetics Brunton

Laurence, Chabner Bruce, Knollman Bjorn, editors. Goodman and Gillman’s The Pharmacological Basis of Theraputics.12ed. USA: McGraw Hills; 2011.p145-68.

[2] Rang HP, Dale M M, Ritter JM, Flower RJ, Henderson G. Pharmacogenetics, Pharmacogenomics & Personalised medicine. Hyde Madelane, Mortimer Alexandra, editors. Pharmacology. 7ed.Britain: Elsevier Churchill Living stone ;2012.p132-8.

[3] http://www.genome.gov/10002077#al-2

[4]http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

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References…[5]

http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126957.pdf

[6]http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm116702.pdf

[7] Semizarov D, Blomme D.Introduction genomics & personalised medicine.Genomics in Drug Discovery and Development .1ed. USA: Wiley; 2009.p1-24.

[8] Dr. Hemant Banga’s Seminar on Pharmacogenetics

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