Download Lecture: Pharmacogenomics

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
Review of Genes
• Genotype:
– The genetic makeup of an
organism
• Phenotype:
– An organisms’ observable traits
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]
Single Nucleotide Polymorphism
• The most common cause
of genetic variation
Polymorphism
“Poly” Many
“Morphe” Form
General Population 94%
• SNPs occur on average
every 1000 bases
• Understanding SNPs has
shown promise for
improving disease
detection and treatments
Single Nucleotide Polymorphism 6%
Examples of SNPs and Disease
SNPs in Beta-globin
Sickle Cell Anemia
SNPs in BRCA1
Predisposed for breast cancer
Single Nucleotide Polymorphisms
Linked SNPs
Causative SNPs
Regulatory Sequence
Coding Region
Protein
Outside gene
Non-coding SNP:
changes amount
of protein
Coding SNP:
changes amino acid
sequence (function)
SNPs Can Change Drug Response
• Pharmacokinetic: changes in drug metabolism
• Pharmacodynamic: changes in drug targets
– enzymes, receptors, or transporters
Genetic
Polymorphisms
Pharmacokinetic
Absorption
Distribution
Pharmacodynamic
Metabolism
Excretion
Receptors
Ion Channels
Enzymes
Immune System
SNPs and CYPs
• Cytochrome P450 enzymes are
commonly found with SNPs
Drug Metabolism
Polymorphism
Substrate
CYP2B6
CYP2C9
CYP2C19
CYP2D6
doxorubicin, nicotine
CYP3A4
erythromycin, HIV protease inhibitors
warfarin, doxorubicin
diazepam, proton pump inhibitors
beta-blockers, anti-depressants, codeine,
tamoxifen
Effects of SNP in CYP2D6
Extensive Metabolizer
Plasma Level of Drug
1: Normal enzyme activity
Poor Metabolizer
Time
2: Decreased enzyme activity
Pharmacokinetics of Tamoxifen
Relapse-free Survival (%)
Mutations Impact Treatment
Outcome
No Polymorphisms on CYP2D6
Extensive n=115
Decreased n=65
Polymorphisms on CYP2D6
P=0.007
Clin Pharmacol Ther. 2008 January; 83(1): 160–166.
Metabolism of Alcohol… 2 Steps
Genetic Polymorphisms and
Differences in Alcohol Metabolism
Genetic Polymorphisms and
Differences in Alcohol Metabolism
ADH
Polymorphism
Metabolism
Rate
Populations with
High Prevalence
ADH1B*1
Slow
Most populations, including most
Caucasians, Mexican Americans, and
Native Americans
Heavy 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)
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
No response
Drug 2
Adverse side effect
Drug 3
Weak response
Drug 4
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 of
the right drug for
the right indication for
the 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 IND
File NDA
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
Pharmacogenomics
Pharmacodynamics
Pharmacokinetics
Gene
SNPs
Haplotype
Phenotype
Genotype
CYPs
Drug