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Publication Date: July 2008
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USING GENETICS TO DRIVE
TREATMENT: A FOCUS ON
WARFARIN

Gregory J. Welder, Pharm.D. candidate



The use of genetics in health care has become
a mechanism for identifying risk. In some cases, ge-
netics are diagnostic for particular disease states such
as Down syndrome, cystic fibrosis, and familial hy-
percholesterolemia.1-3 Patients are commonly asked
about family history as a crude way of estimating
genetic risk which is used in concert with environ-
mental factors to more fully assess clinical risk.
Even with the growing use of imaging and clinical
markers that are available to aid in individualizing
medical care, patients' responses to drug therapies
are variable. The need to predict this variability be-
comes particularly important for pharmacotherapy
that has a narrow therapeutic index or when treating
emergent cases where time to a therapeutic endpoint
is linked to outcomes.
An emerging area to consider in treatment
response are the pharmacogenetics (PGX) of the
treatment modality. PGX is the study of the effects
that a particular gene has on drug response. Another
related term is pharmacogenomics, which evaluates
drug response on a larger, genome-wide scale. The
concept of PGX dates back over 40 years, and picked
up clinical momentum with the completion of the
human genome project.4 The overall idea behind
PGX is to maximize drug therapy while reducing
side effects.
One drug where PGX has proven beneficial is


the anticoagulant, warfarin (Coumadin or Jan-
tovenTM).5 The evidence supporting the benefits and
risks of warfarin has been well documented. The
margin of error between the risks and benefits is nar-
row making warfarin a drug that even with well de-
signed protocols can take weeks to stabilize. This
article will review the concepts of PGX, the data sur-
rounding warfarin use, and the key PGX genes which
explain the variability in warfarin dosing.

PGX: A Brief Overview
Drug variability driven by PGX is largely due
to the pharmacokinetics and the pharmacodynamics
of the medication. Genes primarily responsible for
drug pharmacokinetics are the metabolizing enzyme
genes namely enzymes of the cytochrome p450
(CYP) enzyme system and p-glycoprotein which
affects the absorption of numerous drugs. Pharma-
codynamically, genes that are involved at the drug's
site of action are of interest.
More specifically, PGX looks at different ge-
netic polymorphisms, or genetic changes, within a
gene and how it may predict drug response. Typi-
cally, genetic polymorphisms can include point mu-
tations (a single nucleotide in the sequence of the
gene is changed to another nucleotide), insertions (a
single nucleotide or more is incorporated into the

rI,. ..il


mm


SPharmaNote


VOLUME 23, ISSUE 10 JULY 2008


INSIDE THIS ISSUE:
USING GENETICS TO DRIVE TREATMENT: A Focus
ON WARFARIN


Volume 23, Issue 10 July 2008


PharmaNote







normal gene sequence), and deletions (a single nu-
cleotide or more is removed from the gene se-
quence). These changes to the genetic code can be
neutral in phenotypic effect or they could improve or
hamper the function of the coded protein. These ge-
netic changes are often classified as gene*N where N
is a particular genetic polymorphism with the desig-
nation of 1 given to the functional or normal gene.
Examples include CYP3A5*1 and CYP3A5*3,
where the *1 represents the normal gene and *3
represents a genetic mutation in intron 3 of the same
gene.6

Warfarin: A Narrow Therapeutic Index Drug
The use of warfarin is recommended in pro-
voked and idiopathic deep vein thrombosis or pulmo-
nary embolism, after selective major surgeries, heart
valve replacement, and prophylactically in atrial fib-


rillation to help prevent the risk of cardioembolic
stroke.7'8 Warfarin's efficacy is currently monitored
by using the International Normalized Ratio (INR)
which is a standardization of the prothrombin time.
Warfarin has been linked to beneficial outcomes in-
cluding reduction in stroke and recurrent venous
thromboembolisms (VTEs) with INR's ranging from
2.0-3.5.8 In addition, warfarin has been linked to an
increased rate of serious bleeding with INRs above
4.0.8,9 For PGX, the two genes most documented in
warfarin dosing are CYP2C9 and a gene impacting
warfarin's pharmacodynamic effects, vitamin K ep-
oxide reductase complex subunit 1 (VKORC1).5'7

Warfarin and CYP2C9
Warfarin is extensively metabolized in the
liver to inactive metabolites. The metabolism is
stereoisomer specific with the 2-5 times more potent


Table 1. Genetic Polymorphisms Associated with Warfarin Dose and Occurrence12

Genetic polymorphism Population Minor allele frequency

CYP2C9*2 Whites 10-20%

Blacks 0-2%

Hispanics 7%

Asians 0-2%

CYP2C9*3 Whites 6-10%

Blacks 0-1%

Hispanics 2%

Asians 2-4%

VKORC1 1173C>T Whites 46-48%

Blacks 13-14%

Hispanics Not Reported

Asians 96%

VKORC1 3730G>A Whites 33-38%

Blacks 43-51%

Hispanics Not Reported

Asians 5-10%

PharmaNote Volume 23, Issue 10 July 2008






Figure 1. Absolute Differences in Weekly Warfarin Doses From Initial Dose to Final/Stable Dose5


P-0.035
18
16.1
16 -
14


1 Variant >1 Variant


Wild Type refers to the patients that had normal CYP2C9 and VKORC1 genes based on the three main polymorphisms.
variant allele at any of the three main polymorphisms.


S-warfarin primarily metabolized by CYP2C9 (the
main modulator of in vivo warfarin activity) and the
less potent R-warfarin metabolized by CYP1A2 and
CYP3A4.7 Two common polymorphisms in
CYP2C9 are CYP2C9*2, which causes an amino
acid change of a cysteine for the normally occurring
arginine, and CYP2C9*3, which causes an amino
acid change of an isoleucine to a leucine. These two
alleles cause a reduction in CYP2C9 activity which
would cause less clearance of the more potent S-
warfarin. It has been reported that the necessary
dose reductions for the *2 and *3 alleles have been
as much as 17% and 37% respectively.10 In a study
of 191 patients who were pre-identified with one or
both of these CYP2C9 variants, patients had a
quicker time to first therapeutic INR and stable anti-
coagulation of 2.73 days and 18.1 days respectively
compared to a standard warfarin initiation algo-
rithm.11 Table 1 has the associated allele frequen-
cies for CYP2C9.

Warfarin and VKORC1
Warfarin inhibits the VKOR enzyme on the
Cl subunit preventing the regeneration of vitamin K
epoxide. This in turn prevents the activation of the
coagulant factors II, VII, IX, and X as well as the
anticoagulant proteins C and S. There are two main
genetic polymorphisms associated with warfarin dos-
ing on the gene encoding the Cl subunit: VKORC1


A variant is the occurrence of mutant or


1173C>T and VKORC1 3730G>A. VKORC1
1173C>T is the main polymorphism supported by
the literature and is listed on the current package in-
sert.7 This particular polymorphism's minor allele is
associated with a 44-63% reduction in warfarin
dose.13'14 The minor allele of the VKORC1
3730G>A has been associated with higher mainte-
nance doses of warfarin in some cases by as much as
90%.13 Allele frequencies for these two polymor-
phisms are listed in Table 1.

Using Warfarin's PGX Data for Dosing
There are several studies combining the
CYP2C9*2 and *3 genotypes with the VKORC1
1173C>T in their analyses. The studies have consis-
tently demonstrated that individually these polymor-
phisms, when combined with age and body weight,
add to the predictability in the dosing of warfarin.15,16
One recent randomized study evaluated pro-
spective dosing of warfarin based on either a stan-
dard dosing algorithm or by PGX guided dosing.
PGX guided dosing established a starting dose based
on CYP2C9*2, CYP2C9*3, VKORC1 1173C>T,
age, weight, and gender.5 This study evaluated 206
patients whose dose adjustments were done by an
unblinded anticoagulation pharmacist. There were
no differences in overall out of range INR values be-
tween the groups (primary end point); however, in a
subset analysis of the combined patients with normal


PharmaNote Volume 23, Issue 10 July 2008


A Dose
(InigIi h


12 -
10 -
8 -
6
6 --
4 -
2

0 -


l PG arm
R STD arm


W~id Type


Volume 23, Issue 10 July 2008


PharmaNote






Figure 2. Average Stable Weekly Maintenance Dose of Warfarin by the Number of Variants5


44.7


T7 A


50
45
40
35
30
25
20
15
10


0


a


Wild TY pe I Variant 2Variant 3 Variants 4 Variants


CYP2C9 and VKORC1 and those with multiple vari-
ants across those genes, the PGX guided dosing had
significantly less out of range INRs. The PGX
guided arm, in secondary end point analyses, proved
to better predict the stable dose (Figures 1 and 2),
required less dosing changes, and when doses needed
to be adjusted, the PGX arm required less change in
the dose.

Other Treatments and PGX
PGX has also proven beneficial in the dosing
and treatment choices in several other areas of ther-
apy. In heart failure, P-adrenergic receptor (ADRB)
genetics have been associated with survival, cardiac
remodeling, and left ventricular ejection fraction
with P-blockers.17 The ability of hydrochlorothiazide
to lower blood pressure and reduce hard outcomes
such as myocardial infarction and stroke have been
linked to genetic differences in the adducin 1
(ADD1) gene. s In oncology therapeutics, thiopurine
S-methyltransferase (TPMT) genetic mutations have
been associated with increased toxicity to agents
such as 6-mercaptopurine and azathioprine and thus
the need for lower dosing. Genetic differences in the
genes encoding p-glycoprotein (MDR1), the mu
opiod receptor (OPRM1), and a CYP metabolizing
enzyme (CYP2D6) are linked to opiate efficacy and
side effects in pain management.19' 20 In Alz-
heimer's, apolipoprotein E (APOE) genetics of drugs
such as tacrine, donepezil, and rivastigmine have
been linked to clinical response.21 These examples
merely touch the surface of the studied PGX interac-
tions and begin to lay the groundwork for a poten-


tially new way to dose medications.
Summary
Variability in patient response to therapy makes
it difficult to correctly treat patients and know what
therapy and dose is most appropriate to initiate.
PGX is an emerging area of study that can aid in in-
creasing treatment effectiveness over a shorter
amount of time. Warfarin and the genes encoding its
metabolizing enzyme, CYP2C9, and its site of ac-
tion, VKORC1, is an exciting application of PGX
research. CYP2C9*2 and *3 polymorphisms have
been associated with reduced enzyme activity, and in
vivo, a reduced warfarin maintenance dose. Like-
wise, VKORC1 1173C>T has been associated with
less warfarin to achieve adequate anticoagulation.
The use of PGX information is gaining clinical rec-
ognition as the FDA has approved the use of PGX
data on warfarin's package insert with a subsequent
approval of a lab test (Verigene Warfarin Metabo-
lism Nucleic Acid Test) to assess these genetic poly-
morphisms.22 The role of PGX in clinical therapy
will continue to grow beyond its current applications
in heart failure, hypertension, oncology, pain man-
agement, and dementia.

References
1. Antonarakis SE, Lyle R, Dermitzakis ET, Rey-
mond A, Deutsch S. Chromosome 21 and down
syndrome: from genomics to pathophysiology.
Nat Rev Genet 2004;5:725-38.
2. Castellani C, Cuppens H, Macek M, Jr., et al.
Consensus on the use and interpretation of cystic
fibrosis mutation analysis in clinical practice. J


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Dose
(niagwk)


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Cyst Fibros 2008;7:179-96.
3. Nicholls DP, Cather M, Byrne C, Graham CA,
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4. Evans DA, Clarke CA. Pharmacogenetics. Br
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5. Anderson JL, Horne BD, Stevens SM, et al.
Randomized trial of genotype-guided versus
standard warfarin dosing in patients initiating
oral anticoagulation. Circulation 2007;116:2563-
70.
6. Langaee TY, Gong Y, Yarandi HN, et al. Asso-
ciation of CYP3A5 polymorphisms with hyper-
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7. Bristol-Myers Squibb. Coumadin (warfarin so-
dium) package insert. Princeton, NJ:2007 Nov.
8. The Seventh ACCP Consensus Conference on
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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor
Pharm.D.


El W W W WW W W ^


PharmaNote Volume 23, Issue 10 July 2008


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