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Indiana Institute of Personalized Medicine
Indiana University School of Medicine
Division of Clinical Pharmacology
2
Objectives



A case…
A fundamental change in the medical paradigm
A short primer on pharmacogenomics
◦ SNPs
◦ Metabolism and transport
◦ SNP nomenclature


Some pharmacogenomically important medications
Clinical application
◦ Back to the case…
Originally created for IU Provider CME 9/2013
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Case:

RF is a 58 year-old female with a past medical history
of coronary artery disease, hypertension, and
hypercholesterolemia who presents to her cardiologist
with shortness of breath, and a sensation of a “racing
heart”. Electrocardiogram confirms atrial fibrillation.
Included in RF’s treatment plan is oral anticoagulation
initiation with warfarin.
◦ RF agrees to genetic screening for potential variants that could
affect her warfarin therapy
 Results reveal that she has the heterozygous CYP2C9*2/*3 and
the GA VKORC1 genotype
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DISEASE
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MEDICATION
Patient
Outcome?
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 Patient
outcomes…
◦ Mitigate or cure disease
◦ No effect
◦ Adverse drug event, difficult
to predict
 Sometimes serious
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
Pharmacogenomic Medical Paradigm…
Pharmacogenetic
test
“Personalized Medicine”
Originally created for IU Provider CME 9/2013
Patient
Outcome
-Mitigate or cure
disease
-No serious
adverse drug
events
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Historical milestones
•
Hemolysis in World War II African-American soldiers treated with primaquine
lead to identification of G6PD deficiency
•
In the 1957, Kalow and Gunn discovered subjects homozygous for a gene
encoding an atypical form of pseudocholinesterase had delayed recovery from
succinylcholine
•
1959, Vogel et al. a common genetic variation in the hepatic enzyme Nacetyltransferase was found to cause marked differences in drug half-life and
plasma concentration of isoniazid
•
1977, Eichelbaum et al. identified the CYP2D6 polymorphism
•
2001, Drucker et al. demonstrated remarkable response using imatinib for CML
•
2003, finished version of human genome sequence is completed
•
June 13th, 2013, US Supreme Court rules that human genes cannot be
patented
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

99.5% of the genome between any two individuals
is identical
Mutations that occur in genomic DNA give rise to
genetic variation
◦ When a mutation occurs in at least 1% of individuals in a
population it is termed a “polymorphism”
◦ Most common polymorphism is the single nucleotide
polymorphism or “SNP”
 Occurs when there is a difference in a single nucleotide
 Approximately 90% of all genetic variation is thought to derive from
SNPs
 2/3rd of SNPs involve replacement of cytosine for thymine
 ~10 million SNPs in the human genome, so far…
◦ Much of the research has focused on the characterization of
the SNPs in human genes regulating drug disposition
 Drug metabolizing enzymes
 Intracellular transport of drugs
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
Drug metabolism
◦ Two basic metabolic reactions
 Phase 1 metabolism:
 Cytochrome P450 (CYP450) system
 CYP3A, 2D6, 2C9, 2C19
 Mixed-function oxidases produce more polar compounds
 Phase 2 metabolism:
 N-acetyltransferase, UDP-glucoruoronysltransferase (UGT),
glutathione S-transferase
 Conjugation reactions increase the molecular weight, increases
bulkiness of compounds
Originally created for IU Provider CME 9/2013
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Nature Reviews Drug Discovery

,
9
215-236
(March 2010) | doi:10.1038/nrd3028
Drug transporters are
found in liver, kidney,
intestines, brain and
pancreas
 Two major classes

Uptake


Facilitate translocation of drugs into
cells
 OAT (organic anion transporter)
 SLCO1B1
 OCT (organic cation transporter)
Efflux


Excrete drugs from within cells to
extracellular space
P-gp (p-glycoprotein), MRP2,
MRP3
Originally created for IU Provider CME 9/2013
Giacomini KM et al. Nature Rev Drug Discovery, 2010; 9: 215-236
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Drug metabolism and transport
◦ SNPs can change the protein of a
CYP450 enzyme or transporter
• Leads to altered drug metabolism and/or
transport
• Effects on drug disposition leading to unpredictable
pharmacodynamics
• Drug response?
• Adverse drug event?
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
Nomenclature of SNPs
◦ Phase 1 enzymes:
Individual Member
Superfamily
CYP2C9*2A
Family
Allele
Suballele
Subfamily
◦ Alleles are alternate versions of a gene
◦ *1 allele designation (CYP2C9*1) most commonly refers to the
“wild type” or “normal” enzyme
◦ *2 or greater denote polymorphic alleles and are typically
numbered in order of discovery-validation
 Homozygous designation: CYP2C9*1/*1 (two copies of wild-type allele)
 Heterozygous designation: CYP2C9*1/*2 (one copy of wild-type and one
copy of reduced function allele)
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Nomenclature of SNPs
◦ Phase 2 enzymes and transporters
 Utilizes similar nomenclature
 UGT1A1*1/*1 (homozygous for wild-type)
 SLCO1B1*1/*5 (heterozygous, contains one functional and one reduced function
allele, “C” allele)
◦ Still other nomenclatures…
 Named by haplotype
 VKORC1, “haplotype A”, (G1639A)
 GG, homozygous, (wild-type), normal levels of VKORC1
 GA, heterozygous, lower level of VKORC1
 AA, homozygous, lowest levels of VKORC1
 Named by allele
 SLCO1B1*5
 “C” high myopathy risk allele, “T” other, low myopathy risk alleles
 TT, homozygous, (low myopathy risk)
 CT, heterozygous, (moderate myopathy risk)
 CC, homozygous, (high myopathy risk)
 Human Leukocyte Antigen (HLA)
 HLA-B*5701
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Clopidogrel
◦ Pro-drug, requires CYP2C19 metabolism to become active
◦ CYP2C19 SNPs have been identified leading to different
metabolism phenotypes
 CYP2C19* 1 (wild-type), normal functioning enzyme
 CYP2C19*17, ultra-rapid metabolizer
 CYP19*2, CYP19*3, CYP2C19*4 have little or no functioning
enzyme
 24% Caucasian, 33% African-Americans, 50% of Asians have at
least one loss-of-function allele
 In 227 cardiac patients, Shuldiner et al. found that 21% of
clopidogrel subjects with CYP2C19 LOF SNPs reached study
endpoint (death, non-fatal MI, urgent revascularization) compared
with 10% without the LOF SNPs
Shuldiner AR et al, JAMA, 2009; 302 (8): 849-57.
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Warfarin
◦ Consists of two isomers, S- and R-warfarin
 S-warfarin is more potent and metabolized by CYP2C9
 R-warfarin is metabolized by CYP1A1, 1A2 and 3A4
 Pharmacologic target is VKORC1
◦ Important SNPs
 CYP2C9*1 (wild type): extensive metabolizers
 CYP2C9*2 and *3: poor metabolizers
 Heterozygous CYP2C9*1/*2 or *3: 20-40% lower clearance
 Homozygous CYP2C9*2/*2: 50% lower clearance
 Homozygous CYP2C9*3/*3: 85% lower
clearance
 CYP2C9 SNPs account for ~10-12% of the interindividual variability
 CYP2C9*2: 16% of Caucasians, 1% of Asians and African–Americans
 CYP2C9*3: 7% of Caucasians, 2% of Asians and African-Americans
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Warfarin
◦ Pharmacologic target of warfarin is also polymorphic
 Vitamin K 2,3-epoxide reductase (VKORC1), inhibitory target of
warfarin
 VKORC1 GG, wild-type
 VKORC1 GA, need ~25% lower doses
 VKORC1 AA, need ~50% lower doses
 VKORC1 SNPs account for ~25% of the interindividual variability
 Haplotype A: African-Americans 15%, Caucasians 42%, Asians 90%
◦ CYP2C9 and VKORC1 variants have been estimated to
explain 30-35% of the variability in warfarin dose requirements
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Warfarin
◦ Recent study by Anderson et al. compared two
groups initiated on warfarin therapy

PG-guided: CYP2C9 and VKORC1 genotype
incorporated into a warfarin dosing algorithm, n=504

Parallel controls: Standard of care, n=1,866
Percentage of OOR INRs and % TTR for PGguided dosing algorithms and parallel
(standard dosing) controls.
◦ Investigators found significantly less INRs out-ofrange (OOR) and more time in therapeutic range
(TTR) during the critical 1 to 3 months of warfarin
therapy in the PG-guided compared to control

PG-guided group also had significantly lower
numbers of serious adverse events
(thromboembolism, hemorrhage, death)
◦ Several large trials are underway to investigate
this further

Genetics Informatics Trial of Warfarin to Prevent DVT (GIFT)

Clarification of Optimal Anticoagulation Through Genetics
(COAG)

European Pharmacogenetics of Anticoagulant TherapyWarfarin (EU-PACT)
Originally created for IU Provider CME 9/2013
Anderson J L et al. Circulation 2012;125:1997-2005
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Simvastatin
◦ Drug transporters also
have SNPs
◦ OATP1B1 is a transporter
for entry of simvastatin into
the hepatocyte for
metabolism
 SLCO1B1 is the gene that
encodes this transporter
◦ A genetic variant of
SLCO1B1 (C allele) was
found to be associated
with an increased risk of
statin-induced myopathy in
a study of over 12,000
subjects taking simvastatin
Originally created for IU Provider CME 9/2013
SEARCH Collaborative Group, NEJM 2008;359:789-99
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Tamoxifen
◦ Pro-drug metabolized by CYP2D6 to active endoxifen
 CYP2D6*1, CYP2D6*2 (normal or “extensive” metabolizers)
 Poor metabolizers (PM) CYP2D6*3, *4, *5, *6
 Intermediate metabolizers (heterozygotes)
 One normal and one PM allele (CYP2D6*1/*3)
 Ultra-rapid metabolizers
 3 or more copies of normal alleles due to duplication
 CYP2D6*1/*2/*2
 PMs are found in 7-14% of Caucasians, 14.5% of AfricanAmericans
◦ In a study of early stage breast cancer subjects taking
tamoxifen, Schroth et al. found that the presence of 2
functional CYP2D6 alleles was associated with better clinical
outcomes than those subjects with non-functional or reducedfunction CYP2D6 alleles
Schroth W et al, JAMA, 2009; 302(13): 1429-36
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Abacavir
◦ Associated with a nonspecific “hypersensitivity
reaction” in patients with
the HLA-B*5701 allele
 Fever, rash, constitutional
symptoms, GI and
respiratory symptoms that
worsen with continued
dosing
 Symptoms abate when
abacavir is discontinued
 In US, HLA-B*5701 is found
in 8% of Caucasians, 2.5%
of African-Americans and
~1% of Asians
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Originally created for IU Provider CME
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
Prior examples are only a subset of the
medications with pharmaco-genomic disposition
issues

A 2011 list of the top 200 prescribed medications
by total prescriptions included 17 with
pharmacogenomic information in their FDA
package inserts
◦ Includes the 5th and 7th most commonly prescribed
medications
◦ In 2011, 362 million prescriptions were filled for these 17
medications
◦ Numbers are only expected to increase as pharmacogenomics
and personalized medicine grows
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Interesting, but so what?
How do I utilize this
genetic information for the
patient in my clinic?
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Clinical Pharmacogenetics Implementation Consortium (CPIC)
• Purpose of CPIC is to “translate genetic information into clinical actions and to
make recommendations for actionable pharmacogenetic variants”
• Group of clinical pharmacologists, clinicians and scientists that review all
current literature and develop recommendations and algorithms to guide drug
dosing based on pharmacogenotypes
CPIC prioritizes gene-drug pairs based on community input
and sponsored surveys of the CPIC members, American
Society of Clinical Pharmacology and Therapeutics (ASCPT)
and the public
• CPIC is a frequent contributor to the FDA and endorsed by the AMA, ASHP
• CPIC has evaluated 14 drugs so far with more to follow
 Abacavir, allopurinol, azathioprine, capecitabine, carbamazepine,
clopidogrel, codeine, irinotecan, mercaptopurine, phenytoin, simvastatin,
TCAs, thioguanine, warfarin
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Case:

RF is a 58 year-old female with a past medical history
of coronary artery disease, hypertension, and
hypercholesterolemia who presents to her cardiologist
with shortness of breath, and a sensation of a “racing
heart”. Electrocardiogram confirms atrial fibrillation.
Included in RF’s treatment plan is oral anticoagulation
initiation with warfarin.
◦ RF agrees to genetic screening for potential variants that could
affect her warfarin therapy
 Results reveal that she has the heterozygous CYP2C9*2/*3 and
the GA VKORC1 genotype
Originally created for IU Provider CME 9/2013
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CPIC guideline for warfarin:
Recommended daily warfarin doses (mg/day) to achieve a therapeutic INR based onCYP2C9 and VKORC1
genotype using the warfarin product insert approved by the US Food and Drug Administration
VKORC1
(1639G>A)
CYP2C9*1/*1
(mg)
CYP2C9*1/*2
(mg)
CYP2C9*1/*3
(mg)
CYP2C9*2/*2
(mg)
CYP2C9*2/*3
(mg)
CYP2C9*3/*3
(mg)
GG
5-7
5-7
3-4
3-4
3-4
0.5-2
GA
5-7
3-4
3-4
3-4
0.5-2
0.5-2
AA
3-4
3-4
0.5-2
0.5-2
0.5-2
0.5-2
Reproduced from updated warfarin (Coumadin) product label.
Clin Pharmacol Ther, 2011, 90: 625-29.
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Conclusions

Pharmacogenomic medicine is
a powerful tool to inform drug
selection and clinical decisionmaking
◦ Has demonstrated potential to
improve efficacy and safety of
medications

As more clinical data
emerges and genotyping
costs fall, there will be
increasing utilization and
presence in clinical medicine
"Here's my sequence...”
New Yorker magazine
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