Personalized medicine

Dumontier::BIOL4301:Personalized Medicine
Personalized
Medicine
Michel Dumontier, Ph.D.
Associate Professor of Bioinformatics
Department of Biology, Institute of Biochemistry, School of Computer Science
Carleton University
Ottawa Institute for Systems Biology
Ottawa-Carleton Institute for Biomedical Engineering
Nov 18, 2010

“If it were not for the great
variability among individuals,
medicine might as well be a
science and not an art”
Sir William Osler, 1892

SNPs – a major source of variation
• Single Nucleotide Polymorphisms
(SNPs)
– Single base change in DNA
AAGCCTA
AAGCTTA
– SNPs arise as a consequence of
mistakes during normal DNA replication
– Average frequency 1/1000bp
• Other sources of variation
– Insertions, deletions, translocation,
duplications, repeats
– copy number variation is a major
element
SNP
Deletion
Translocation
Insertion
Most Common

Human Variation
• In human beings, 99.9 percent bases are same.
• Remaining 0.1 percent (~3M bases) makes a
person unique.
– Different attributes / characteristics / traits
• how a person looks,
• diseases he or she develops.
• These variations can be:
– Harmless (change in phenotype)
– Harmful (diabetes, cancer, heart disease, Huntington's
disease, and hemophilia )
– Latent (variations found in coding and regulatory
regions, are not harmful on their own, and the change
in each gene only becomes apparent under certain
conditions e.g. susceptibility to lung cancer)

Personalized Medicine
The ability to offer
• The Right Drug
• To The Right Patient
• For The Right Disease
• At The Right Time
• With The Right Dosage
Genetic and metabolic data
will allow drugs to be
tailored to patient
subgroups

Benefits of Personalized Medicine
• Better matching patients to drugs instead of “trial
and error
• Customized pharmaceuticals may eliminate life-
threatening adverse reactions
• Reduce costs of clinical trials by
– Quickly identifying total failures
– Favourable responses for particular backgrounds
• Improved efficacy of drugs

Personalized Medicine : BiDil
• Combination pill containing two medications for
heart failure, cardiovascular disease, and/or
diabetes.
• Clinical trials did not show overall benefit across
entire population.
• Subgroup of patients showed best overall benefit
– BiDil approved solely for use in African-descent patients.
Controversial!

PGx
• Pharmacokinetics
– What the body does to the drug
– dose, dosage regimen, delivery form
– Drug fate: Absorption, distribution, metabolism, and elimination
of drugs (ADME)
• Pharmacodynamics
– What the drug does to the body
– Biochemical and physiological effects of drugs
– mechanism of drug action
– relationship between drug concentration and effect
• Pharmacokinetics and pharmacodynamics are essential to assess
the drug efficacy.

PGx + genetics/genomics
• Pharmacogenetics
– The effect of genetic variation on drug response.
• Pharmacogenomics
– The application of genomics to the study of human
variability in drug response.
• Pharmacogenetics and pharmacogenomics are
expected to play an important role in the development of
better medicines for populations and targeted therapies
with improved benefit/risk ratios for individuals

Cytochrome P450 Enzymes
In bacteria, fungi, insects, plants, fish, mammals
Catalyze monooxygenation reaction:
RH + 2H+
+O2 + NADPH
 ROH + H2O + NADP+
Act on:
– Endogenous substrates (cholesterol,
steroids, fatty acids)
– Exogenous (drugs, food additives,
environmental toxins)
Involved in
– Production of steroids
– Metabolism of fatty acids, prostaglandins,
leukotrienes, retinoids
– Activation or inactivation of therapeutic
agents
– Enzyme activation/inhibition resulting in
drug-drug interactions, adverse events

Drug-Metabolizing Enzymes
Pharmacogenomics: Translating Functional Genomics into Rational
Most DME have clinically relevant polymorphisms
Those with changes in drug effects are separated from pie.
Phase I: modification of functional groups Phase II: conjugation with endogenous substitutents

CYP enzymes are involved in the metabolism of
clinically important drugs
CYP Enzyme Examples of substrates
1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17β-Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R-
Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
S. Rendic Drug Metab Rev 34: 83-448, 2002

S. Rendic Drug Metab Rev 34: 83-448, 2002
Red indicates enzymes important in drug metabolism
Factors Influencing Activity and Level of CYP Enzymes
Nutrition
1A1;1A2; 1B1, 2A6, 2B6,
2C8,9,19; 2D6, 3A4,5
Smoking 1A1;1A2, 2E1
Alcohol 2E1
Drugs
1A1,1A2; 2A6; 2B6; 2C;
2D6; 3A3, 3A4,5
Environment
1A1,1A2; 2A6; 1B; 2E1;
3A3, 3A4,5
Genetic
Polymorphism
2A6; 2C9,19; 2D6;

Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537
Nortriptyline (anti-depressant)
Pharmacogenetics

Dumontier::BIOL4301:Personalized MedicineWeinshilboum, R. N Engl J Med 2003;348:529-537
Use of probe drugs to determine metabolic
activity due to CYP2D6 variants
Antihypertensive debrisoquin decreases blood pressure

CYP3A4
• Abundant in liver and intestines
and accounts for nearly 50% of
CYP450 enzymes.
• Activity can vary markedly among
members of a population
– Constitutive variability is ~5-fold
but can increase to 400-fold
through induction and inhibition
• Activity affected by other drugs:
– Grapefruit juice is an inhibitor
Felodipine is a calcium channel
blocker (calcium antagonist), a
drug used to control hypertension
(high blood pressure)
5mg tablet
with juice

Quantitative Structure-Activity
Relationship (QSAR)
• find consistent relationship between biological activity
and molecular properties, so that these “rules” can be
used to evaluate the activity of new compounds.
• extract features (hydrophobicity, pK, van der Waals radii,
hydrogen bonding energy, conformation)
• build mathematical relationship f(activity|features)
• automatically assesses the contribution of each feature
• can be used to make predictions on a new molecule

3D QSAR for CYP3A4

3D QSAR for CYP3A4 with known
substrates

Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002
CYP3A4 mediated Drug-Drug Interaction
PXR: pregnane X receptor; RXR: retinoid X receptor
• Protect against xenobiotics
• Diverse drugs activate through heterodimer complex
• Cause drug-drug interactions

Codeine
Metabolism
Gasche Y et al. Codeine intoxication associated with ultrarapid
CYP2D6 metabolism. NEJM 2004
• 80% codeine normally converted
to glucuronide, eliminated by
kidney.
• 5-10% codeine is metabolized
into morphine by CYP2D6
• inhibition of CYP3A4 or rapid
metabolic variants of CYP2D6
during renal failure would
show toxicity
– 7% of caucasians have a
nonfunctional CYP2D6 variant
– <2% are CYP2D6 ultrarapid
metabolizers which may suffer
from opioid intoxication

Diagnostics
AmpliChip CYP450: Range
of drug metabolism
phenotypes is observed for
individuals based upon the
cytochrome P-450 genes

Known side effects
Unavoidable Avoidable
Medication
errors
Product quality
defects
Preventable
adverse
events
Injury
or death
Remaining
uncertainties
• Unexpected side effects
• Unstudied uses
• Unstudied populations
Sources of risk from drug products
FDA: Center for Drug Evaluation and Research
2005 - Report to the Nation

LIPITOR:
Known Side Effects
• Lipitor blocks the
production of
cholesterol in the body.
• May reduce risk of
hardening of the
arteries, which can lead
to heart attacks, stroke,
and peripheral vascular
disease

Drug recalls are surprisingly common
Drug Recalls
191
226 248
352 354
254
215
401
60
53
34
88
72 156 83
88
71
101
248
316
176
72
0
300
600
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Fiscal year
Number
Prescription Over-the-counter

Many reasons for drug recalls
Reported Drug Quality Defects
Other, 9%
Contamination/
sterility, 3%
Fill problem,
4%
Packaging, 6%
Delivery
system, 10%
Product defect,
14% Formulation/
substitution,
22%
Adverse drug
reports, 18%
Labeling, 14%
Fiscal year 2005

Treatment for Acute Pain
increased risk of heart attack and stroke
(after 18 months)
VIOXX: Unknown Side Effects

Vioxx targets prostaglandin
biosynthesis
• Prostaglandins, derivatives of C20
fatty acids, often trigger pain,
fever, and inflammation.
• Aspirin, Ibuprofen,
acetominaphen are non-steroidal
anti-inflammatory drugs
(NSAIDS) that inhibit
prostaglandin H2 synthase
(A.K.A. COX) – no pain.

• 3 isoforms: COX-1, COX-2, COX-3.
• COX-1 constitutively expressed
• COX-2 only expressed in response to inflammation
• Drugs were designed to fit into COX-2 active site
channel, but not COX-1 (20% smaller channel)
• Vioxx & Celebrex lack non-specific side effects of
NSAIDS, but Vioxx caused cardiac side effects & was
withdrawn in 2004

in silico Drug Discovery
• Need 3D structure
• Scan a virtual library of small molecules and “dock” them
to a site of interest on a protein structure
• Predict binding energy
• Filters thousands of compounds relatively quickly
• Top hits can be used for more rigorous
computational/experimental characterization and
optimization

Successful drug discovery strategies involve
computational and experimental approaches
oral
bioavailabity
binding
Less
pain
Fewer side
effects
repeat…

synthesis
of compound
↓
manipulation of
structure to get
better drug
(greater efficacy,
fewer side effects)Aspirin

"When you're studying human genetics, you're studying the information that
goes into the making of man and how that information flows from one
generation to the next. To be able to do that well, you have to know the
population structure. We can basically take the list that includes everyone in the
country or 2,000 people with schizophrenia. We can know within minutes
exactly how everyone is related to everyone else, which is key for being
able to study the genetics of anything in a sensible manner."
deCODE
Genetics in
Reykjavik,
Iceland.
Country-wide genotyping and family tree
reconstruction

deCODE Genetics
For example, deCODE has used the Icelandic family tree to look at people who
are taking statins. Approximately 10,000 people in Iceland take statins, but
about 2,000 of those don't respond. The list of patients who don't respond can
be run through the genealogy database. "I can tell you that they are related to
each other, and we can get families that have a structure that allows us to map
a gene that indicates a lack of response to statins."

Things to Consider
• Does my doctor know enough about
genomic medicine to be advising me?
– Are there genetic counselors available?
• Will the test only be for this condition?
– What if I am susceptible to another disease?
• Who will know about this?
– Doctors… insurance companies?
• How exactly will the results be kept secure
and in confidence?

How much will this cost?
• More drugs may succeed in clinical trials due to
positive outcome for smaller subset
– Will pharma attempt to recoup costs with a pricier drug?
• Will public health cover the costs of genetic
testing?
– Reduce overall health cost due to fewer ADRs
– Should we determine clinically validated genes or
should we sequence the genome?
• How will insurance premiums be affected?

There is still lots to figure out…
• Science still early. Limited data in public domain.
• Many variations not clinically significant
• Expensive to test for genotype (currently)
• Ethical issues in testing individual genotype
• Unclear how to deliver information to the
practitioner

Personalized Medicine:
What’s your take?

dumontierlab.com
michel_dumontier@carleton.ca

Personalized medicine

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