Cours Pharmaco

"Personalised medecine: how genetic screening
can predict efficacy of a particular drug"
Pr. Kaoutar BENTAYEBI

Do Now
Discuss the following questions with the

person (or people) next to you:
1. What are the potential benefits to knowing more

about your likelihood of developing a genetic
disease?
2. What are the possible downsides to knowing?
3. Aside from health and medical information, what

else might you be curious to learn about from
your DNA?
Genetics is getting more personal
because
Genetics is learning
gettingabout
moreourpersonal
own
DNA is rapidly becoming
because learning about our own
inexpensive and accessible.
DNA is rapidly becoming
inexpensive and accessible.
DNA analysis can provide:
• Insights about our health, behavior, family history

and other traits.
• Highly personal information with personal, social

and familial impact.
• Information about genes and traits available to

consumers through their doctor.
Why might personal genetics matter to you?
• Genome analysis available for under $600 dollars

• Takes just a few weeks to complete
• Transforming medical care for the next generation
Image: James Hart, CC BY-NC-ND 2.0

The Beery twins’ story highlights
the promise of personalized medicine
http://dystonia.thebeerys.com/
The Beery twins’ story highlights
the promise of personalized medicine
Genome sequencing has already had real-world impact on

patients, including twins Alexis and Noah Beery. The twins
exhibited a number of developmental delays and were diagnosed
with cerebral palsy at the age of two. However, their mother,
Retta, never felt that this diagnosis was correct, particularly since
their symptoms worsened over the course of the day. Through
their mother’s research and advocacy, the twins were diagnosed
with a genetic disorder called dopa-responsive dystonia and
began taking a medication that seemed to successfully treat the
condition. However, some symptoms persisted and escalated,
particularly for Alexis, including serious breathing problems. The
Beery family had the twins' genomes sequenced, leading to the
identification of a mutation in the SPR gene which, when
disrupted, causes deficiencies in two neurotransmitters, called
dopamine and serotonin. Upon treatment to restore dopamine
and seratonin, the twins’ symptoms quickly improved, permitting
them to resume full, active lives.
Personal choices based on
genetic information
• Angelina Jolie reveals

she chose to undergo a
double mastectomy.
• Jolie had a genetic test

and found she carried a
mutation in the BRCA1
gene. Doctors
estimated there was a
very high chance she
would get breast cancer.
Image: Gage Skidmore, CC BY-SA 2.0

http://www.post-gazette.com/lifestyle/2006/03/29/
DNA-tests-locate-genetic-branches-on-African-Americans-family-trees/stories/200603290216
Genome sequencing technology
Applied Biosystems Oxford Nanopore

3730 DNA Analyzers MinION
2002 2014
(left) Photo by Jurvetson, flickr, CC BY 2.0; (right) Oxford Nanopore Technologies

What could you learn from genetic testing?
- Risk for conditions including:
• Alzheimer’s Disease
• Heart Disease
• Cancer
- Carrier Status
- Which medications could work

best for you and/or which
could harm you
- Ancestry
How does direct-to-consumer
genetic testing work?
1. Order kit online. 2. Spit into tube 3. The lab 4. Customer

and send to lab. analyzes DNA. receives results.
Note: Some tests require a doctor’s approval. In this case, results are
typically sent to both the customer and the doctor, so they may discuss.
What is the Personal Genome
Project about?
PGP Harvard PGP UK
PGP Canada
Some variants predicting severe
effects in the PGP-10
Some variants predicting severe effects in the PGP-10
Variant Putative effect

Participant
PGP5 (hu9385BA) PKD1-R4276W Autosomal dominant polycystic kidney disease
PGP6 (hu04FD18) MYL2-A13T Hypertrophic cardiomyopathy
PGP9 (hu034DB1) SCN5A-G615E Long QT syndrome
PGP10 (hu604D39) PKD2-S804N Autosomal dominant polycystic kidney disease
PGP10 (hu604D39) RHO-G51A Autosomal dominant retinitis pigmentosa
Personalized medecine the answer?
Why Personalised medicine?
Pharmacogenetics or pharmacogenomics?
Adverse Drug Reactions (ADR)
• The most drugs are not or partially effective in the 60% of the treated patients
• Side effects are responsible for

– 100,000 death
– 2 million hospitalisations
– 100 billion USD cost for healthcare in USA
– 50%- of the cases is related genetics
Major drugs ineffective for many

How drug is metabolised?
- Pharmacokinetics (PK): The process by which a drug is

Absorbed, Distributed,Metabolized, and Eliminated (ADME)
by the body.
- Pharmacodynamics (PD): The study of how a drug acts on a

living organism, including the pharmacologic response and the
duration and magnitude of response observed relative to the
concentration of the drug at an active site in the orgaism
- PK: What the organism does to the drug
- PD: what the drug does to the organism

How drug is metabolised?
DrugDrug metabolism
metabolism usuallyconsists
usually consists of
of two
twophases
phases
Phase 1
Non synthetic reactions for all types of drugs involve metabolic modifications which may
give more active compounds than original
Ex: Oxidation : methyl alc. is oxidized to formic acid==> toxic; phenacetin is oxidized to
paracetamol; tremorine is oxidized to oxotremorine==>tremor inducing drug
Reduction : trichloroethanol is reduced to chloral hydrate
Hydrolysis : Acetyl salicylate is hydrolyzed to acetate & salicylate
Phase 2
Synthetic reactions for only some drugs involve conjugation to give water sol. subs. easily
to be excreted. Conjugation is done with glucoronic acid (mainly) ,acetic acid ,glycine ,or
sulphate Ex: Benzoic acid + Glycine =====> Hippuric acid
Drug metabolism usually consists of two phases
How does genetic variation affect drug effect?
- Body uses enzymes to modify drug

substances
- Many metabolic enzymes are

polymorphic
- 59% of drugs that cause ADR are

metabolized by polymorphic enzymes
Effects of Polymorphisms of Drug-Metabolizing Enzymes on Plasma Concentration

Examples of Polymorphism linked to drug response
Examples of Polymorphism linked to drug response
- Families: 17 families in humans
- Subfamilies: 42 sub-families in humans
- Enzyme/gene: 55 genes and 29 pseudogenes in humans
- Cytochrome P450 superfamily of

polymorphic enzymes
- Found all over the body
- Catalyse most Phase I oxidative
ractions
- Major enzymatic activity occurs in
hepatic CYP (liver)
- Also expressed in the brain, lung,
kidneys, intestines, monocytes,
macrophages, lymphocytes…
- Relevant in the bioactivation and
metabolism of 75% of drugs
Examples of SNP linked to drug response
Case study WARFARIN
Personalized WARFARIN Dosis
- One-third of thrombosis patients metabolize their warfarin

dose differently that expected due in large part to variations
of 2 genes, VKORC1 and CYP2C9
- VKORC1 SNP, such as 1639>A allele, indicate that a patient

will respond well to a lower dose of warfarin
- CYP2C9*2 and CYP2C9*3 alleles encode SNP variants of

CYP2C9 with reduced efficiency in degrading warfarin
- Warfarin labeling suggesting genetic testing of VORC1 and

CYP2C9 is the first indication of personalized dosing being
approved by the FDA
Example 1: Pharamcogenetic claim {Dosage}
Example 2: Pharmacogenetic claim {Efficacy}
Challenges in personal genetics
1. How likely is it you or your doctor can take action

based on genetic information?
2. How might this information impact you and your

family?
3. How can we ensure access for everyone?
4. Will people understand that our environment (health

care, family, society, etc.) also shapes who we are?
The classical therapy:therapy:
The classical Uniformisation
Uncertain
Observation Treatment
respond
Independently from the heterogeneity of the population try to get in large cohorts
positive results/risk ratio with the treatment (clinical utility)
Targeted therapy:
Differenciate, diagnostics and drug co-development
Testing Predicted
Observation Treatment
(Biomarker) respond
Targeted therapies help by identificatioon of the patients with the best respond and less side effects
Biomarkers are such diagnostic tools, wich may predict the therapeutic respond to a certain drug
Wang L et al. N Engl J Med 2011;364:1144-1153.
Thank you for your
attention

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"Personalised medecine: how genetic screening

can predict efficacy of a particular drug"

Pr. Kaoutar BENTAYEBI

Discuss the following questions with the

1. What are the potential benefits to knowing more

2. What are the possible downsides to knowing?

3. Aside from health and medical information, what

• Insights about our health, behavior, family history

• Highly personal information with personal, social

• Information about genes and traits available to

• Genome analysis available for under $600 dollars

Image: James Hart, CC BY-NC-ND 2.0

Genome sequencing has already had real-world impact on

• Angelina Jolie reveals

• Jolie had a genetic test

Image: Gage Skidmore, CC BY-SA 2.0

Applied Biosystems Oxford Nanopore

(left) Photo by Jurvetson, flickr, CC BY 2.0; (right) Oxford Nanopore Technologies

- Risk for conditions including:

- Which medications could work

1. Order kit online. 2. Spit into tube 3. The lab 4. Customer

Some variants predicting severe effects in the PGP-10

Variant Putative effect

• Side effects are responsible for

Major drugs ineffective for many

- Pharmacokinetics (PK): The process by which a drug is

- Pharmacodynamics (PD): The study of how a drug acts on a

- PK: What the organism does to the drug

- PD: what the drug does to the organism

- Body uses enzymes to modify drug

- Many metabolic enzymes are

- 59% of drugs that cause ADR are

Effects of Polymorphisms of Drug-Metabolizing Enzymes on Plasma Concentration

- Cytochrome P450 superfamily of

- One-third of thrombosis patients metabolize their warfarin

- VKORC1 SNP, such as 1639>A allele, indicate that a patient

- CYP2C9*2 and CYP2C9*3 alleles encode SNP variants of

- Warfarin labeling suggesting genetic testing of VORC1 and

1. How likely is it you or your doctor can take action

2. How might this information impact you and your

3. How can we ensure access for everyone?

4. Will people understand that our environment (health

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- CYP2C92 and CYP2C93 alleles encode SNP variants of