Pharmacogenetics&

Pharmacogenomics

Personalized Medicine

Drugs and Genes• Pharmacogenetics:

– Study of the genetic factors that influence an organism's reaction to a drug

• Pharmacogenomics: – Development of drug therapies to compensate for

genetic differences in patients

• Genotype: – The genetic makeup of an

organism

• Phenotype:– An organisms’ observable traits

Review of Genes

Human Genome is Variable

Human Genome is Variable• Contains 3x109 base pairs of DNA

– 3 billion!

• Between 2 people (except identical twins) the rate of genetic variation (individuality) is about 0.1%[0.1% of 3 billion = 3 million base pair differences]

• The most common cause of genetic variation

• SNPs occur on average every 1000 bases

• Understanding SNPs has shown promise for improving disease detection and treatments

Single Nucleotide PolymorphismPolymorphism

“Poly” Many“Morphe” Form

General Population 94%

Single Nucleotide Polymorphism 6%

Examples of SNPs and Disease

SNPs in Beta-globinSickle Cell Anemia

SNPs in BRCA1Predisposed for breast cancer

Protein

Single Nucleotide Polymorphisms

Regulatory Sequence Coding Region

Coding SNP:changes amino acidsequence (function)

Outside gene

Linked SNPs

Non-coding SNP:changes amountof protein

Causative SNPs

SNPs Can Change Drug Response

• Pharmacokinetic: changes in drug metabolism• Pharmacodynamic: changes in drug targets

– enzymes, receptors, or transporters

Genetic Polymorphisms

Pharmacokinetic

Absorption Distribution Metabolism Excretion

Pharmacodynamic

Receptors Ion Channels Enzymes Immune System

SNPs and CYPs

• Cytochrome P450 enzymes are commonly found with SNPs

Drug Metabolism

Polymorphism Substrate

CYP2B6 doxorubicin, nicotine

CYP2C9 warfarin, doxorubicin

CYP2C19 diazepam, proton pump inhibitors

CYP2D6 beta-blockers, anti-depressants, codeine, tamoxifen

CYP3A4 erythromycin, HIV protease inhibitors

Effects of SNP in CYP2D6

1: Normal enzyme activity

2: Decreased enzyme activity

Extensive Metabolizer

Pla

sma

Leve

l of

Dru

g

Time

Poor Metabolizer

Pharmacokinetics of Tamoxifen

Mutations Impact Treatment Outcome

No Polymorphisms on CYP2D6

Polymorphisms on CYP2D6

Clin Pharmacol Ther. 2008 January; 83(1): 160–166.

Extensive n=115

Decreased n=65

Rel

apse

-fre

e S

urv

ival

(%

)

P=0.007

Metabolism of Alcohol… 2 Steps

Genetic Polymorphisms and Differences in Alcohol Metabolism

ADH Polymorphism

Metabolism Rate

Populations with High Prevalence

ADH1B*1 SlowMost populations, including most Caucasians, Mexican Americans, and Native AmericansHeavy drinkers

ADH1B*2 Fast Most Asians, 25% of Jews, and some Hispanics

ADH1B*3 Fast African-Americans and 6% of Mission Indians (S. West California)

Genetic Polymorphisms and Differences in Alcohol Metabolism

23andMe

Better Drug Discovery with Pharmacogenetics & Pharmacogenomics

• Increase drug efficacy

• Eliminate adverse drug reactions

• Ensure success for drug approval in clinical trials

• Increase efficiency of clinical trials

Drug Treatment

Available Drugs

Drug 1

Drug 2

Drug 3

Drug 4

No response

Adverse side effect

Weak response

Strong response

Currently best treatment determined by trial and error.

Future genomics may enable us to pick the right drug the first time.

Yesterday’s Medicine

Tomorrow’s Medicine

Personalized Medicine

The right dose ofthe right drug forthe right indication forthe right patient at the right time.

Personalized Medicine: Cancer

Many factors contribute to tumor formation.

Breast Cancer is a Perfect Model

Pharmacogenomics: Gene Candidate to Drug Treatment

Human epidermal growth factor receptor-2 (HER2) in breast cancer cells

Herceptin in Clinical Trials

Cancer Results from a Combination of Genomic Changes

Drug Discovery

The Clinical Trial Process

Safe in humans?

Does the treatment

work?

Better than current

treatment?

More info on the

approved treatment

File NDAFile IND

Less than 1 in 10 Drugs in Clinical Trials Obtain a NDA

In a study of 14 clinical trials, 20-75% of subjects got no benefit

Streamlining of Clinical Trials is the Future

Pharmacogenetics and Pharmacogenomics Summary

1. SNPs in coding and non-coding regions can alter the function or expression of an enzyme that metabolizes drugs

2. Pharmacogenetics impacts the kinetics and dynamics of drugs.

3. Personalized medicine will help treat patients according to their genetic profile, increase drug efficacy, and reduce side effects

4. Designing clinical trials based on SNP profiles can reduce FDA approval time for drugs

Concept Map PharmacogenomicsPharmacodynamics PharmacokineticsGeneSNPsHaplotypePhenotype GenotypeCYPsDrug