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Pharmacogenetics

&
Personalized Medicine

Courtesy of Felix W. Frueh US FDA

Personalized Medicine
Medicine is personal:
We are all different.
Some of our differences translate into how we react to drugs as individuals.
This is why personalized medicine is important to everyone.

Why does someone need twice the standard dose to be effective?


Why does this drug work for you but not me?
Why do I have side-effects and you dont?
Why do some people get cancer and others dont?
Why is anecdotal information irrelevant to your own health and
treatment?

Is Medicine a Science or an Art?


If it were not for the great variability among individuals, medicine
might well be a science, not an art.

Sir William Osler, Physician 1892


Johns Hopkins School of Medicine
Johns Hopkins Hospital
Father of modern medicine

The Goal of Personalized Medicine


The Right Dose of

The Right Drug for


The Right Indication for
The Right Patient at
The Right Time.

Courtesy Felix W. Frueh

R!

Same symptoms,
Same findings,
Same disease?

Different patients
Same drug
Same dose

Differential drug
efficacy
At a recommended prescribed dosage

Different Effects

a drug is efficacious in most.


not efficacious in others.
harmful in a few.

Lack of efficacy
Unexpected side-effects

People react differently


to drugs
One size does not fit all

Genotyping

Toxic responders
Non-responders
Responders

Patients with drug


toxicity
Patients with nonresponse to drug therapy

Patient population with


same disease phenotype

Patients with normal


response to drug therapy

Same symptoms,
Same findings,
Same disease?

Different patients
Same drug
Same dose

Why does drug


response vary?
Genetic
Differences
G
A

SNP

Different Effects
Ethnicity
Age
Pregnancy
Genetic factors
Disease
Drug
interactions

Possible Reasons:
Individual variation
By chance

Why does drug response vary?


Genetic variation
Primarily two types of genetic mutation events create all forms
of variations:
Single base mutation which substitutes one nucleotide for another
--Single nucleotide polymorphisms (SNPs)

Insertion or deletion of one or more nucleotide(s)


--Tandem Repeat Polymorphisms
--Insertion/Deletion Polymorphisms

Polymorphism: A genetic variation that is observed at a


frequency of >1% in a population

R!

Single nucleotide polymorphisms (SNPs)


SNPs are single base pair positions in genomic DNA at which
different sequence alternatives (alleles) exist wherein the least
frequent allele has an abundance of 1% or greater.
For example a SNP might change the DNA sequence

AAGCTTAC
to ATGCTTAC

SNPs are the most commonly occurring genetic differences.

Single nucleotide polymorphisms (SNPs)


SNPs are very common in the human population.
Between any two people, there is an average of one SNP
every ~1250 bases.
Most of these have no phenotypic effect
Venter et al. estimate that only <1% of all human SNPs impact protein function (lots
of in non-coding regions)

Some are alleles of genes.

Tandem Repeat Polymorphisms


Tandem repeats or variable number of tandem repeats (VNTR)
are a very common class of polymorphism, consisting of variable
length of sequence motifs that are repeated in tandem in a
variable copy number.
Based on the size of the tandem repeat units:
Microsatellites or Short Tandem Repeat (STR)
repeat unit: 1-6 (dinucleotide repeat: CACACACACACA)
Minisatellites
repeat unit: 14-100

Insertion/Deletion Polymorphisms
Insertion/Deletion (INDEL) polymorphisms are quite
common and widely distributed throughout the human
genome.

Due to individual variation


20-40% of patients benefit from an approved
drug
70-80% of drug candidates fail in clinical trials
Many approved drugs removed from the market
due to adverse drug effects
The use of DNA sequence information to
measure and predict the reaction of individuals
to drugs.
Pharmacogenetics

Personalized drugs

Faster clinical trials


Less drug side effects

Pharmacogenetics
Study of interindividual variation in DNA sequence related
to drug absorption and disposition (Pharmacokinetics) and/or
drug action (Pharmacodynamics) including polymorphic
variation in genes that encode the functions of transporters,
metabolizing enzymes, receptors and other proteins.
The study of how people respond differently to medicines
due to their genetic inheritance is called pharmacogenetics.

Correlating heritable genetic variation to drug response


An ultimate goal of pharmacogenetics is to understand how
someone's genetic make-up determines, how well a medicine works
in his or her body, as well as what side effects are likely to occur.

Right medicine for the right patient

Pharmacogenetics VS.
Pharmacogenomics
Pharmacogenetics: Study of variability in
drug response determined by single
genes.
Pharmacogenomics: Study of variability in
drug response determined by multiple
genes within the genome.

Pharmacogenetics

Genetic Polymorphism:
SNPs; INDEL; VNTRs

The study of variations in genes that


determine an individuals response to drug
therapy.

Common variation in DNA sequence (i.e.


in >1% of population)

Potential Target Genes are those that encode:


Drug-metabolizing enzymes
Transporters
Drug targets

Determinants of Drug Efficacy and Toxicity


A patients response to a drug may depend on factors that can vary according
to the alleles that an individual carries, including :

dose administered

Pharmacokinetics

ABSORPTION
concentration in
systemic circulation

DISTRIBUTION

drug in tissues
of distribution

ELIMINATION
concentration at
site of action

Pharmacodynamic factors
- Target proteins
- Downstream messengers

Clinical response

Efficacy

- Absorption
- Distribution
- Metabolism
- Elimination

metabolism and/or excretion

Pharmacologic effect

Toxicity

Pharmacokinetic factors

Pharmacodynamics

Genotype VS. Phenotype


The interaction between genotype and
phenotype has often been described using a
simple equation:
genotype + environment phenotype

A slightly more nuanced version of the


equation is:
genotype + environment + randomvariation phenotype

Pharmacogenetics & Pharmacogenomics


Pharmacogenetics: The role of genetics in drug responses.
F. Vogel. 1959

Pharmacogenomics: The science that allows us to predict a


response to drugs based on an individuals genetic makeup.
Felix Frueh, Associate Director of Genomics, FDA

Courtesy Felix W. Frueh

Pharmacogenetics & Pharmacogenomics


Pharmacogenetics: study of individual gene-drug interactions, usually one
or two genes that have dominant effect on a drug response (SIMPLE
relationship)
Pharmacogenomics: study of genomic influence on drug response, often
using high-throughput data (sequencing, SNP chip, expression, proteomics
- COMPLEX interactions)

Courtesy of Michelle Whirl-Carillo

Purine Analogs:
A Case Study in Pharmacogenetics
6-mercaptopurine, 6-thioguanine, azathioprine
Used to treat lymphoblastic leukemia, autoimmune disease,
inflammatory bowel disease, after transplant
Interferes with nucleic acid synthesis
Therapeutic index limited by myelosuppression

(treatment limited by immune suppression side effect)

6-mercaptopurine

6-thioguanine

azathioprine

Metabolism of 6-MP

LWang and RWeinshilboum, Oncogene 25, 1629-1638 (2006)

Pharmacogenetics: A Case Study

Courtesy of Michelle Whirl-Carillo

Pharmacogenetics: A Case Study

Courtesy of Michelle Whirl-Carillo

Pharmacogenetics: A Case Study

Courtesy of Michelle Whirl-Carillo

Thiopurine S-methyl Transferase Activity and


Personalized Dosage

Eichelbaum et al., Annu. Rev. Med. 2006.57:119-137.

Drug efficacy is questioned..

Percentage of non-responders

"Here's my sequence... [New Yorker]


Are we ready?
Not quite yet! We
need:
Comprehensive data
Affordable genotyping
tools
Professional Education
Solving ethical issues!

Any questions?

Thank you

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