Colin Slides

MEDG421: Pharmacogenomics
Colin Ross, MSc PhD

Assistant Professor, Dept. Pediatrics, Medical Genetics
Child & Family Research Institute
University of British Columbia
February 2, 2016
Pharmacogenomics Outline
i. Introductory Case Report Example
1. Core Concepts of Pharmacogenomics

Adverse Drug Reaction
Pharmacogenomics
2. Example of Pharmacogenomics
Warfarin dosing
Azathioprine
3. Pharmacogenomics Research
Canadian Pharmacogenomics Network for Drug Safety
Technology Platforms
SNP genotyping
DNA sequencing
Example: Anthracycline cardiotoxicity

Extra Example if time: Cisplatin-induced deafness
Case Report from 2005

Drug: Anthracycline
chemotherapy
Case Report: Year 2005

A previously healthy 8year-old child presented
with neuroblastoma to
B.C. Childrens Hospital
Began anthracycline
(doxorubicin)
chemotherapy
Prior to last cycle of
treatment, visited B.C.
Childrens Hospital for
routine CT scan, but
became unwell during
scan
Case Report
During CT scan:
Developed serious cardiac
dysfunction with virtually no
cardiac output
ECMO Unit
Intubated and rushed to ICU

Placed on extracorporeal
membrane oxygenation (ECMO)
for 3 weeks
1 year later received a heart
transplant
First transplanted heart rejected
Child received a second heart
transplant
Currently in cancer remission
Heart Transplant
Lifelong Consequences of Severe ADRs

in the Treatment of Cancer
Canada: > 700,000 cancer survivors
USA: > 10,000,000 cancer survivors
75% of cancer survivors suffered at least 1 ADR
40% of cancer survivors have had a severe ADR
(life-threatening, or disabling)
1.
Geenan et al, JAMA, 2007
Case Report: 2016

+ Pharmacogenomic Testing
Case Report 2016

1 year old presenting with a
paraspinal mass behind heart,
elevated urinary
catecholamines, and MIBG
positive mass suggestive of
neuroblastoma.
Biopsy confirmed stage IV
neuroblastoma
Treatment protocol calls for
treatment with anthracyclines
Applied predictive pharmacogenetic test

before anthracyclines administered:
PGx-cardiotoxicity risk profile for patient
PATIENT
100%
89% Cardiotoxicity Risk
Risk of Cardiotoxicity (%)
90%
80%
Same profile
as previous
case
(~2% of population.
Risk estimate based
upon 9 patients.
Includes carriers of
1+ RARG and 1+
UGT risk variants).
70%
60%
50%
40%
30%
10%
0%
(~13% of population.
Risk estimate based upon 80
patients. Includes carriers of
1 risk variant, or 2 risk + 1
protective variant).
20%
14% Risk
protective SLC28A3 variant.)
0%
20%
(~2% of population.
Risk estimate based
upon 11 patients.
Includes carriers of 2
RARG risk variants).
Risk estimate based upon
356 patients. Includes noncarriers, and carriers of 1 risk
+ 1 protective variant).
40%
60%
80%
100%
Patient Anthracycline-Induced Cardiotoxicity PGx Risk (Percentile)
Case Report 2016

Pharmacogenomic testing was conducted to
determine risk of anthracycline cardiotoxicity
Highest risk group for anthracycline toxicity (carries both
UGT1A6 and homozygous for RARG high risk variants)
Estimated genomic risk of cardiotoxicity: 89%
In addition to high genetic risk of cardiotoxicity, the

patient was at high clinical risk for cardiac toxicity
Young age
Radiation to the tumor would result in high exposure of
focal radiation to the heart
Case Report 2016

Clinicians presented patient at Tumor Board
Reviewed risks to patient (both clinical and genomic)
Reviewed literature for role of anthracyclines in high
risk neuroblastoma in infants
Decision made to avoid anthracyclines completely

Use a treatment protocol where only 1 dose of
anthracycline is part of the study and then omit this
dose
Patient completed therapy 2 years ago and is

alive and well, in remission and with normal
cardiac function
Future
Clinical genome sequencing
Costs falling
$100 genome?, $0 genome?
Rapid pharmacogenomic testing

Point-of-care testing
Pharmacogenomics
Warfarin dosing
Azathioprine
SNP genotyping
DNA sequencing

Example: Cisplatin-induced deafness
The Ideal Medication

Effectively treats or
prevents disease
Has no adverse effects
Paradox of Modern Drug Development

1. Clinical trials provide evidence of efficacy
and safety at usual doses in populations
Safe & Effective
2. Physicians treat individual patients who can

vary widely in their response to drug therapy
Safe & Effective
No Response
2500 years ago
Hippocrates
Different [medications] for
different patients, for the
sweet ones do not benefit
everyone, nor do the
astringent ones, nor are all
the patients able to drink
the same things"
- Hippocrates
The Father of Medicine
500 years ago

Paracelsus - The Father of Modern Toxicology
Pioneered the use of chemicals and minerals in medicine
All things are poison

and nothing is without
poison, only the dose
permits something not
to be poisonous."
Paracelsus
(1493-1541)
100 years ago
Sir William Osler

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)
Individual variability in drug response

can have serious consequences
Stevens-Johnson Syndrome (SJS)

Definition

Any unwanted, negative consequence
associated with the use of given
medications
Differs from the meaning of "side-effect",
as this last expression might also imply
that the effects can be beneficial
Adverse Drug Reactions

ADRs are the 5th leading cause of death in the USA
Over 100,000 fatal ADRs in hospitalized patients each year
Over 2,000,000 serious ADRs in hospitalized patients per year
ADRs cause 7% of all hospital admissions (USA, UK)

Occur in 15% (11-22%) of hospitalized patients (USA, UK)
Cause 6% of deaths in hospital (Spain)
ADR Health Care Costs: $78-177 billion annually (USA)
Exceeds the annual cost of medications
June 3, 2008
12% of patients rushed to Vancouver

General Hospital ER have adverse
reactions to medications.
Zed et al, Can Med Assoc J, 2008
50% of newly approved therapeutic health

products have serious ADRs, discovered
only after the product is on the market
- Health Canada, 2007
Factors Contributing to
Variability in Drug Response
Gender Weight
Ethnicity
Diet
Compliance
Concomitant Disease
Genetic Factors
20-95%
Concomitant Drugs
Age
Patient genotype is currently a major unknown

factor in the prescribing of medicines
Pharmacogenomics
Definition: The study of the interaction between
an individuals genetic make-up and his or her
response to a particular drug.
Simpler definition:
The right medication,
For the right patient,
At the right dose,
At the right time.
Single Nucleotide Polymorphisms (SNPs)

[ T/G ]
[A/G]
Variations in DNA (frequency >1%)
[T/C]
[T/C]
SNPs make up >90% of genetic variations

When comparing 2 people:
1 SNP occurs every 600-1200 bp
(= 5-10 million differences, ~99.9% identical)
>40 million validated SNPs (Feb 2016)
Validated SNPs numbers: rsID: rs328, rs12201199
SNP/CNVs can alter the amino acid sequence of the encoded
proteins, alter RNA splicing, alter transcription, and modify
susceptibility to epigenetic modifications
No one size fits all
Pharmacogenomics
Warfarin dosing
Azathioprine
SNP genotyping
DNA sequencing

Example #1
Warfarin
Warfarin
Most commonly prescribed oral anticoagulant drug
Used by 2 million people each day in the USA
Warfarin inhibits blood coagulation:

Inhibits VKORC1 (Vitamin K Epoxide Reductase)
VKORC1 normally generates Vitamin K
Vitamin K (Koagulation Factor) is essential for the
activation of coagulation precursors (factor II, VII, IX, X)
Warfarin
Inhibits
VKORC1
Vitamin K
of
Activation
coagulation
factors
Clotting
Warfarin
Narrow therapeutic window
Can take months of clinic visits to determine a
patients ideal dose
Too high a dose
Too low a dose
Formation of
dangerous blood clots
(1-8% of patients)
Serious risks of excessive

bleeding and intracranial
hemorrhage
(5-35% of patients)
Fanikos et al . Thromb Haemost 2005
Warfarin Pharmacogenomics
Variants in the CYP2C9 and VKORC1 genes
account for 57-63% of variance in warfarin dose
CYP2C9
CYP2C9 breaks down warfarin
20% of people carry low activity variants (e.g. *2, *3)
resulting in decreased warfarin elimination, and require a
lower dose
VKORC1 (Vitamin K Reductase)

VKORC1 in pathway that generates Vitamin K
Vitamin K is essential for coagulation
Warfarin inhibits VKORC1 = decreased vitamin K =
decreased coagulation
2 common haplotypes of the VKORC1 gene, A and B.
Depending on ancestry, 2-79% of people carry low
activity variants and require a lower dose
Warfarin Pharmacogenomics
Warfarin
Inhibits
VKORC1
Vitamin K
of
Activation
coagulation
Clotting
factors
CYP2C9
Inactivation of warfarin to
4- and 6-hydroxywarfarin
Warfarin
CYP2C9
Inhibits
VKORC1
Vitamin K
Activation of
coagulation
factors
Clotting
Excessive
Bleeding
Inactivation of warfarin to
4- and 6-hydroxywarfarin
Frequent CYP2C9 and VKORC1 Genetic Variations Cause

Low Enzyme Activity: Require Lower Warfarin Dose
FDA voted to revise the Warfarin label:

New label recommends genetic testing
In the USA, Warfarin PGx testing estimated to:

Save $1.1 billion/year in health care costs
Prevent 17,000 strokes/year
Prevent 85,000 serious bleeding incidents
(McWilliam et al. 2006)
Example #2
Azathioprine-induced
Severe Myelosuppression
Azathioprine
Inhibits purine synthesis
First line therapy for over 50 years
Cancer
Acute lymphocytic leukemia
Autoimmune diseases
Rheumatoid Arthritis
Ulcerative Colitis
Psoriatic Arthritis
Multiple Sclerosis
Autoimmune Hepatitis
SLE
Inflammatory bowel disease
Imuran (Canada, UK)

Azasan (USA)
Azathioprine Adverse Drug Reaction

1-2% of patients suffer irreversible severe or fatal
myelosuppression
10-20% suffer moderately severe
myelosuppression
Blood counts traditionally used to monitor therapy
Simplified Metabolism of Azathioprine

KEY CONCEPT:
~5-11% of individuals
have low levels of
TPMT activity
Azathiopurine
HPRT
Not present in
haematopoietic
cells
Inactive
Metabolite
Inactive
Metabolite
Active Metabolites
(Disrupt DNA transcription
and replication)
Thiopurine Methyltransferase (TPMT): Inactivates Azathioprine

5-11% of the people have reduced TPMT activity
Patients with low TPMT treated with Azathioprine accumulate
excessive active drug metabolites = Massive overdose
Increased risk of severe/possibly fatal myelosuppression
Increased risk of infection
% Subjects
Prevalence of TPMT Genotypes
TPMT activity (U/ml RBC)
0.3-1% carry two copies

of low activity variants:
TPMT*2 A80P
TPMT*3C Y240C
No drug inactivation
Lethal Overdose
5-10% carry one copy of

a low activity variant:
TPMT*2 A80P
TPMT*3C Y240C
Less drug inactivation

Overdose
85% carry normal

activity TPMT:
Normal drug inactivation

Normal drug efficacy
Prevalence of TPMT Genotypes

% Subjects
~5% carry
increased
activity
TPMT:
Increased
TPMT activity (U/ml RBC)
0.3-1% carry two copies

of low activity variants:
TPMT*2 A80P
TPMT*3C Y240C
No drug inactivation
Lethal Overdose
5-10% carry one copy of

a low activity variant:
TPMT*2 A80P
TPMT*3C Y240C
Less drug inactivation

Overdose
drug
inactivation
Reduced
drug
effectiveness
85% carry normal

activity TPMT:
Normal drug inactivation

Normal drug efficacy
St. Judes Azathioprine Dose

Alteration Study
Dosing of Azathiopurines was changed,
based on genotype of TPMT variants
Patients with reduced TPMT activity (one
low activity variant) received 50% dose
Patients with no TPMT activity (two low
activity variants) received only 10% dose
Standard dose of Azathioprine administered to

all patients: Potentially lethal for some patients
Toxicity
Drug Exposure
Same Dose of
Azathioprine
Administered
To All
Patients
Homozygous
Carriers
Homozygous
Carriers
Het.
Carriers
Het. Carriers
(200 mg/m2/wk)
Drug
exposure increased
in variant carriers
TPMT
Potentially lethal
myelosuppresion in
variant carriers
normally inactivates
azathioprine metabolites
1%: homozygous for low activity TPMT variants

10%: heterozygous for low activity TPMT variants (Y240C, A154T, A80P)
Wild type (normal)
Black et al Ann. Intern. Med. 2005
Pharmacogenetic testing of TPMT significantly

reduces the risk of Azathioprine toxicity while
cure rates remain the same
Genotype-based
Dose Administered
125
Het.
Carriers
Drug Exposure
Toxicity
Homozy.
Carriers Het.
Carriers
Homozy.
Carriers
Dose reduced for
TPMT variant
carriers
Equivalent drug
exposure for all

patients
Cure rates the
Aza tolerated
without toxicity
Lethal ADRs
avoided
same
Black et al Ann. Intern. Med. 2005
Pharmacogenomics
Warfarin dosing
3. Examples of Pharmacogenomics Research

SNP genotyping
DNA sequencing
Example: Anthracycline-induced cardiotoxicity

How Can The Causes of

be Unraveled?
Human Genome: ~3 billion nucleotides.

Typed out 1 per mm = 3,000 km long
Human Genome: ~3 billion nucleotides.

Typed out 1 per mm = 3,000 km long x 2 copies
3000 km
Vancouver
Thunder Bay
3000 km
Goose
Bay

be Unraveled?
1.
Well-defined
patients who
have
developed
similar ADRs
(or response
to drugs)
(+ controls)
2.
3.
Methods to
accurately
interrogate the
genome to
identify
associated
genetic
variants
Strategies to
validate
identified
associations

be Unraveled?
1.
Well-defined
patients who
have
developed
similar ADRs
(or response
to drugs)
(+ controls)
2.
3.
Methods to
accurately
interrogate the
genome to
identify
associated
genetic
variants
Strategies to
validate
identified
associations
Problem: Over 95% of ADRs are not reported

e.g.
2 studies of drug-induced
toxic epidermal necrolysis
being treated in burn units
Q: What % of these ADRs
were reported ?
4% ADR Reporting Mittman et al., Drug Safety 2004;27(7):477-87.
2.5% ADR Reporting Rzany et al., J Clin Epidemiol 1996;49(7):769-73
The Canadian Pharmacogenomics

Network for Drug Safety
Hypothesis
Genetic differences in drug metabolism genes cause
a significant portion of serious ADRs
Goal
To identify the genetic factors that cause specific
ADRs, and to develop diagnostic tests that will
predict and avoid these severe ADRs
2005-2016 ADR Cases: >8,000

ADR Controls: >70,000

be Unraveled?
1.
Well-defined
patients who
have
developed
similar ADRs
(or response
to drugs)
(+ controls)
2.
3.
Methods to
accurately
interrogate the
genome to
identify
associated
genetic
variants
Strategies to
validate
identified
associations
Genomic Analyses
1. Study Design
2. Genotyping
3. Sequencing
Case-Control Study Design

Patients On Drug

Patients On Drug
ADR Patients
Control Patients

Patients On Drug
Genomic Analyses
ADR Patients
Control Patients

Patients On Drug
Genomic Analyses
ADR Patients
Genotyped for 7 variants
Control Patients

Patients On Drug
Genomic Analyses
ADR Patients
Control Patients
Odds Ratio: 17
p-value 0.000023
Genotyping
Technology for Genome-wide

Genotyping Studies:
Rapidly perform up to 5 Million
genetic tests per DNA sample
Genome-Wide SNP Genotyping
SNP
Array
50 million beads
on one slide
Genome-Wide Genotyping
SNP
Array
DNA target
capture probes
affixed to beads:
50 bp
complementary
to SNP region
SNP 1
SNP 2
SNP 3
Patient
DNA
Add patient DNA

sample to array
SNP
Array
SNP 1
SNP 2
SNP 3
Patient
DNA
Exactly matching
DNA from patient
binds probe
SNP
Array
G
SNP 1
SNP 2
SNP 3
Patient
DNA
Exactly matching
DNA from patient
binds probe
SNP
Array
G
SNP 1
SNP 2
SNP 3
Patient
DNA
Single-nucleotide
extension
(biochemical reaction)
SNP
Array
G-C
SNP 1
-G -G
SNP 2
-A
SNP 3
Patient
DNA
Single-nucleotide
extension
(biochemical reaction)
Fluorescently
Labeled
SNP
Array
G-C
SNP 1
-G -G
SNP 2
-A
SNP 3
Patient
DNA
SNP
Array
C/C
Patient
DNA
SNP
Array
A/A
C/A
C/C
Patient
DNA
SNP
Array
End Result:
Highly accurate genotype data for
1000s to millions of genetic
variations throughout the genome
Green Signal
Raw
Fluorescence
Intensity Data
AA
AB
Yellow
Intermediate
Signal
BB
Red Signal
Genotype Text
Output
SNP 1
SNP 2
SNP 3
SNP 4
AA
TT
GG
GC
Raw SNP Data (n = 480)
Reproducibility
>99.99%
16 miscalls out of
178,860 genotype calls
(58 patient DNA
replicates)
0 miscalls out of
50,688 genotype calls
(16 control DNA
replicates)
DNA Sequencing
Year 2002
DNA Sequencing
Factory with
1,000 DNA Sequencers
Year 2016
1 Bench Top
High-Throughput
DNA Sequencer
10+ years to sequence

the human genome
Cost: $2.7 billion
1 day to sequence
the human genome
Cost: ~$2,000
DNA Sequencing vs. Genotyping

Whole Genome Sequence
$2,000/patient
Identifies all novel and
known variants
Technology improving
$150 per patient

Identifies known rare
and common variants
i.e., 500,000 tests
DNA Sequencing vs. Genotyping

Whole Genome Sequence
$2,000/patient
Identifies all novel and
known variants
Technology improving
$300 per patient

Identifies known rare
and common variants
5 million tests
Genomics Technology Developments
10,000+
Standard DNA
Sequencers
Illumina Next
Generation Highthroughput
DNA Sequencing
Platform

be Unraveled?
1.
Well-defined
patients who
have
developed
similar ADRs
(or response
to drugs)
(+ controls)
2.
3.
Methods to
accurately
interrogate the
genome to
identify
associated
genetic
variants
Strategies to
validate
identified
associations
Not covered today
(Basically:
replication &
functional validation
of findings)
CPNDS Priority ADR Targets

In Progress:
Anthracycline-induced cardiotoxicity
Cisplatin-induced deafness
Codeine-induced infant mortality
Life-threatening skin reactions
Vincristine-induced neuropathy
Statin-induced muscle toxicity
Interferon- toxicity
Warfarin-induced bleeding/thrombosis
many
Example #3
(Research Example)
Anthracycline-induced
cardiotoxicity
Pharmacogenomics
Warfarin dosing
3. Examples of Pharmacogenomics Research

SNP genotyping
DNA sequencing
Example: Anthracycline-induced cardiotoxicity

(If time: Example: Cisplatin-induced deafness)
Anthracyclines
e.g., Doxorubicin, Daunorubicin
Highly effective cancer therapy
Significantly increased childhood cancer
survival rates
Administered to 60-70% of childhood
cancer patients (leukemias & solid tumors)
Adults: breast cancer, sarcoma,
lymphoma, leukemia, and others
Over 900,000 patients receive each year
Case Report
A previously healthy 8year-old child presented
with neuroblastoma to
B.C. Childrens Hospital
Began doxorubicin
chemotherapy
Prior to last cycle of
treatment, visited B.C.
Childrens Hospital for
routine CT scan, but
became unwell during
scan
Case Report
During CT scan:
Developed serious cardiac
dysfunction with virtually no
cardiac output
ECMO Unit
Intubated and rushed to ICU

Placed on extracorporeal
membrane oxygenation (ECMO)
for 3 weeks
1 year later received a heart
transplant
First transplanted heart rejected
Child received a second heart
transplant
Currently in cancer remission
Heart Transplant
Anthracycline-Induced Cardiotoxicity
Since 1967, recognized that
anthracyclines can cause fatal cardiac
toxicity (Tan et al., Cancer, 1967)
ECMO Unit
57% of patients develop clinical

cardiotoxicity
5-16% of patients suffer serious
cardiomyopathy and heart failure
Toxicity can occur at doses < 300 mg/m2

While some patients tolerate >1000 mg/m2
May require intra-ventricular assist

device or heart transplant
Increased severity in children,
especially less than 4 years old
72% mortality rate for severe cases
(BC Cancer 2010)
Kremer et al. N Engl J Med. 2004; Canadian Cancer

Statistics 2007; Mariotto et al. J Natl Cancer Inst. 2002
Heart Transplant
Classification of Anthracycline-Cardiotoxicity
Controls
No cardiotoxicity, SF 30%, 5yr follow-up

Grade 1 toxicity:
Shortening fraction 27-30% or

Resting ejection fraction 50-60%
Grade 2 toxicity: Moderate to severe cardiotoxicity

Shortening fraction 15-26% or
Resting ejection fraction 40-50%
ADR
Cases
Grade 3 toxicity: Symptomatic congestive heart failure

Shortening fraction < 15% or
Resting ejection fraction < 40%
Grade 4 toxicity: Congestive heart failure requiring
heart transplant or ventricular assist device

Resting ejection fraction < 20%
Modified National Cancer Institute Common Terminology Criteria for Adverse Events v3.0
With modified Grade 1 from 24-30% SF to 27-30% SF
Study Design
Stage 1
Discovery
Canadian
patients of
European
Ancestry
N = 280 patients: 32
cases and 248 drugmatched controls
740k
Genome
-wide
Array
Stage 2
Replication
Stage 3
Replication
Functional
Validation
Dutch patients of
European Ancestry
Patients of
Worldwide
Ancestries
Cell models
N = 96 patients: 22
N = 80 patients (19
cases, 61 controls)
Stage 1 - Discovery Cohort:

Identified 8 associated genomic regions
Stage 1
Odds Ratio: 7.0 (2.9-17.0)
P-value: 5.0x10-6
Stage 2 - European Replication Cohort:

Replicated 1 associated genomic region
RARG
Stage 1
Odds Ratio: 7.0
P-value: 5.0x10-6
Stage 2
Odds Ratio: 4.1
P-value: 0.0043
N = 96 patients: 22
Stage 3 Worldwide ancestry Replication Cohort:

Replicated 1 associated genomic region
RARG
Stage 1
Odds Ratio: 7.0
P-value: 5.0x10-6
Stage 2
Odds Ratio: 4.1
P-value: 0.0043
N = 96 patients: 22
Stage 3
Odds Ratio: 9
P-value: 0.0012
N = 80 patients: of
worldwide
ancestries
RARG is linked to the pathogenesis of

anthracycline-cardiotoxicity through TOP2B
In cells, we found:
- RARG normally
represses TOP2B =
protective
- RARG-variant does
Aminkeng et al. 2015
not repress TOP2B =

increased TOP2B =
anthra. cardiotoxicity
Top2b Repression
(Normalized )
Zhang et al. 2012
Previously found in mice:

- Reduced TOP2B = protective
- Increased TOP2B = anthracycline cardiotoxicity
- But no common genetic variation in TOP2B in
humans
Normal
RARG
Variant
RARG
-1
-2
-3
-4
***
n = 12
*** = P < 0.0001
Nature Genetics, Sept., 2015
Prediction model stratifies patients based on genetic

risk of anthracycline cardiotoxicity
100%
90%
80%
(~2% of population.
Risk estimate based
upon 9 patients.
1+ RARG and 1+
UGT risk variants).
70%
60%
50%
40%
30%
10%
0%
20%
14% Risk
0%
20%
(~2% of population.
Risk estimate based
upon 11 patients.
40%
60%
80%
100%
Findings implemented: Pilot Program, BC Childrens Hospital

Pharmacogenomic risk profile of anthra-cardiotoxicity
100%
90%
80%
Based
on 600
patients
CASE
REPORT
PATIENT
(~2% of population.
Risk estimate based
upon 9 patients.
1+ RARG and 1+
UGT risk variants).
70%
60%
50%
40%
30%
10%
0%
20%
14% Risk
0%
20%
(~2% of population.
Risk estimate based
upon 11 patients.
40%
60%
80%
100%
Potential Clinical Options for

Personalized Anthracycline Therapy
Depending on risk prediction, clinician could take different
actions:
Low Risk
Echocardiogram follow-up as usual
Intermediate Risk
Intensify echocardiogram follow-up
e.g. patients in rural centres often miss appointments
High Risk
Alternative medication (e.g. mitoxantrone) or dose
Add cardioprotectant (e.g. dexrazoxane)
Start treatment with ACE-inhibitors or beta-blockers to
prevent further damage
Summary of Pharmacogenomics
Avoid adverse drug reactions
Maximize drug efficacy for individual patients
Pharmacogenetic Profile:
All Patients with

Same Diagnosis
High risk of ADR (50%):

treat with alternative
drug or dose
Moderate risk of ADR (12.5%):

treat with alternative drug or
dose, or increased monitoring
10% risk of
adverse reaction
Low risk of ADR (0%):

treat with conventional dose
Examples of drugs with FDA label changes based

on pharmacogenomic information (=140)
Medication
Indication
Gene
Adverse Event
Azathioprine
Cancer
TPMT*3A,B,C
Severe neutopenia,
Infection
Warfarin
Anticoagulant CYP2C9, VKORC1
Severe bleeding,
thrombosis
Irinotecan
Cancer
UGT1A1*28
Severe neutropenia
Abacavir
HIV
HLA-B*5701
Hypersensitivity
reaction
Carbamazepine
Epilepsy
HLA-B*1502
Severe SJS/TEN skin

reaction
Codeine
Analgesic
CYP2D6-UM
Intoxication, Death in
breastfeeding infants
Atomoxetine
ADHD
CYP2D6
Severe toxicity
http://www.fda.gov/cder/genomics/genomic_biomarkers_table.htm
Nilotinib
Leukemia
UGT1A1*28
Hyperbilirubinemia
Rifampin
Antibiotic
NAT2
Hepatotoxicity
In the Future
Advances in technology opening the
doors to understanding the genetic
factors of ADRs
Whole Genome Sequencing
Routine genotyping of millions of SNP variants
Lower health care costs through ADR

prevention
ADRs now exceed the cost of medications in
USA/Canada
Improved medication safety

Safer and More Effective Treatment Options
Study Questions
Sample Question 1
A doctor identifies a subgroup of patients (~10% of
the population) who lose feeling in their fingers and
toes after they take a new experimental cold
medicine. Can you help the doctor design a study or
experiment to identify (if any) the cause of this
unusual reaction? (focus on genetic factors)
Sample Question 2
A doctor prescribes azathioprine to a patient. The
patient asks for the genetic TPMT test, but the
doctor doesn't know what he's talking about. Explain
to the doctor why the patient would want this test
before they receive azathioprine?

Colin Slides

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MEDG421: Pharmacogenomics

Colin Ross, MSc PhD

1. Core Concepts of Pharmacogenomics

Example: Anthracycline cardiotoxicity

Case Report from 2005

Case Report: Year 2005

Intubated and rushed to ICU

Lifelong Consequences of Severe ADRs

Geenan et al, JAMA, 2007

Case Report: 2016

Case Report 2016

Applied predictive pharmacogenetic test

Risk of Cardiotoxicity (%)

45% Cardiotoxicity Risk

39% Cardiotoxicity Risk

21% Cardiotoxicity Risk

Patient Anthracycline-Induced Cardiotoxicity PGx Risk (Percentile)

Case Report 2016

In addition to high genetic risk of cardiotoxicity, the

Case Report 2016

Decision made to avoid anthracyclines completely

Patient completed therapy 2 years ago and is

Rapid pharmacogenomic testing

Example: Anthracycline cardiotoxicity

The Ideal Medication

Has no adverse effects

Paradox of Modern Drug Development

Safe & Effective

2. Physicians treat individual patients who can

2500 years ago

500 years ago

All things are poison

100 years ago

Sir William Osler

Individual variability in drug response

Stevens-Johnson Syndrome (SJS)

Adverse Drug Reaction

Adverse Drug Reactions

ADRs cause 7% of all hospital admissions (USA, UK)

12% of patients rushed to Vancouver

50% of newly approved therapeutic health

Patient genotype is currently a major unknown

Single Nucleotide Polymorphisms (SNPs)

Variations in DNA (frequency >1%)

SNPs make up >90% of genetic variations

No one size fits all

Example: Anthracycline cardiotoxicity

Warfarin inhibits blood coagulation:

Serious risks of excessive

Fanikos et al . Thromb Haemost 2005

VKORC1 (Vitamin K Reductase)

Frequent CYP2C9 and VKORC1 Genetic Variations Cause

FDA voted to revise the Warfarin label:

In the USA, Warfarin PGx testing estimated to:

Inflammatory bowel disease

Imuran (Canada, UK)

Azathioprine Adverse Drug Reaction

Simplified Metabolism of Azathioprine

Thiopurine Methyltransferase (TPMT): Inactivates Azathioprine

Prevalence of TPMT Genotypes

TPMT activity (U/ml RBC)

0.3-1% carry two copies

5-10% carry one copy of

Less drug inactivation