Pharmacogenetic Testing Benefits Compounding Pharmacy

452
International Journal of Pharmaceutical Compounding
Vol. 17 No. 6 | November/December 2013
www.IJPC.com
Feature
(PHARMACOGENETICS)
ABSTRACT Pharmacists must consider all factors when dosing medication for a
patient. Until recently, however, one key piece to this puzzle was missing—genetics.
This invisible piece of the puzzle can now be utilized with pharmacogenetic
testing. By using pharmacogenetic testing, the compounding pharmacist will
be able to better predict disease risk as well as the pharmacodynamic and
pharmacokinetic actions of the prescriptions their patients are taking.
Pharmacogenetics is poised to become the standard of care that not
only physicians are embracing, but pharmacists can utilize to better per-
sonalize their patient’s needs.
AllauthorsareaffiliatedwithIversonGenetic
Diagnostics,Inc.,Bothell,Washington.
Brian Fichter, PharmD
Tom Heintzelman, PhD
Sawan Hurst, MS
Dorothy Fitzsimmons, RN
Christina Mailloux, PhD
Clinical Utility of
Pharmacogenetic
Testing in Compounding
Pharmacy

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Pharmacogenetics
metabolizing drugs and other xenobiotics.
Many of these liver enzymes are highly
affected by individual SNP variations in
the DNA. Since genes come in pairs, one
from each parent, a patient can have two
normal genes (no variants), one variant
(heterozygous), or two variant genes
(homozygous). Patients with no variants
have normal enzyme function, but
patients with one or two variants can have
enzymes that function more or less than
normal enzymes. This affects how the
body metabolizes drugs, which in turn
affects the plasma levels of a drug in the
blood. Levels that are too high can cause
adverse drug reactions (ADRs), and levels
that are too low can make treatment inef-
fective. With more than 4 billion prescrip-
tions being dispensed every year, millions
of patients are either under- or over-
treated, and there are over two million
serious ADRs yearly.4 Due to this, geno-
typing to guide pharmacological treatment
is becoming the gold standard in patient
care and an important step in the person-
alized medicine revolution. Compounding
pharmacists are highly qualified special-
ists in personalized medicine and are
uniquely positioned to offer pharmacoge-
netic testing as part of their practice.
Within the context of this article, we will
discuss three clinical applications of phar-
macogenetic testing, all of which have
valuable relevance to the practice of com-
pounding pharmacy.
BREAST CANCER RISK
PREDICTION
One important aspect of compounding
pharmacy is hormone replacement
therapy (HRT). HRT has been used for
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As a health sciences discipline, pharma-
cists provide patient care that optimizes
medication therapy and promotes health,
wellness, and disease prevention.1 Phar-
macists have an obligation to contribute to
the generation and utilization of state-of-
the-art knowledge that advances health
and quality of life.1 The clinical applica-
tion of pharmacogenetics is one example
of such an advancement of innovative
knowledge. Pharmacogenetics refers to
genetic differences in metabolic pathways
that can affect an individual's response to
drugs in terms of therapeutic effect as well
as adverse effects.2 Although the terms
pharmacogenomics and pharmacogenetics
tend to be used interchangeably, pharma-
cogenetics is regarded as the clinical
testing of genetic variations that gives rise
to differing responses to drugs, whereas
pharmacogenomics is the broader applica-
tion of genomic technology associated
with drug discovery. Despite the fact that
pharmacogenetic and pharmacogenomic
concepts have been around for hundreds
of years,3 it is only in recent years that we
have seen a rapid increase in the main-
stream application of these sciences.
Genes, the units of heredity present on
DNA strands inherited from one’s parents,
are the blueprints for all individual traits.
They code for everything from obvious
characteristics such as hair color and
height to less obvious characteristics such
as blood type. Within every person’s genes
lie small differences in the DNA code,
with each unique version of the gene
referred to as an allele. One common type
of difference, called a single nucleotide
polymorphism (SNP; pronounced “snip”),
occurs when one base in the DNA code is
changed. Sometimes SNPs are neutral,
meaning they have no effect on the body
and the resulting characteristic is
unchanged. In other cases, this single
change in the DNA code can alter the
genetic blueprints such that it results in
everything from small alterations to dra-
matic effects on the characteristics.
Genes also code for enzymes, the chemi-
cal workhorses of the body, including all
liver enzymes that are responsible for

454
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Pharmacogenetics
decades by post-
menopausal and
peri-menopausal
women to help curb
many of the symp-
toms of menopause
such as sweating
and hot flashes. As
many as two
million women in
the U.S. use cus-
tomized hormones
for menopause
symptoms.5 Compounding pharmacy provides the service of cus-
tomizing these individualized medications, a service that industry
cannot and will not meet.5 Customization allows pharmacists to
tailor treatment to an individual woman’s needs, an important
application of personalized medicine. Notably, these hormones are
bioidentical hormones and, as the name suggests, are, therefore,
molecularly identical to the hormones a woman produces in her
body. This makes HRT more natural. To even further personalize
patient experience with HRT, many compounding pharmacists also
monitor hormone levels with saliva-based testing.
Although HRT is prescribed for millions of women, the complica-
tions of HRT, including risk of breast cancer development, are not
insignificant. Studies show estrogens are a prime risk factor for the
development of breast cancer,6-9 and breast cancer risk is higher in
women with early menarche and late menopause because of a
longer exposure to estrogens. Experiments on estrogen metabo-
lism,10-12 formation of DNA adducts,13,14 mutagenicity,15,16 cell
transformation, and carcinogenicity19,20 have implicated certain
estrogen metabolites, especially the catechol estrogen
MAMMOGRAPHY IMAGE SHOWING A NORMAL
BREAST ON THE LEFT AND A CANCEROUS
BREAST ON THE RIGHT.
4-hydroxyestradiol (4-OHE2) metabolite, to react with DNA via
their quinone, causing mutations and initiating cancer.
Genetics and gene variants have also been known to play a role in
breast cancer development. The most notorious of these mutations
are in the BRCA1 and BRCA2 tumor suppressor genes, which play a
key role in repairing DNA damage. Harmful DNA variants cause
these enzymes to work more poorly and allow for more DNA
damage to accumulate. Over time, this can lead to cancer, and
women with BRCA mutations are at a much higher risk for develop-
ment of ovarian and breast cancers. Although genetic testing for
these genes has gained media attention as of late because of high-
profile celebrities testing positive, in actuality, mutations in BRCA1
or BRCA2 only account for about 5% to 10% of all breast cancer
cases.21 Thus, most women that develop breast cancer have risk
factors other than mutations in the BRCA genes.
Since estrogen exposure has been deemed so important to breast
cancer development, current models of risk prediction are based
mainly on surrogates of cumulative estrogen exposure such as age,
age at menarche, and age at first live birth.22-26 These tests,
however, don’t directly reflect mammary estrogen metabolism and
exposure to carcinogenic estrogen metabolites. Researchers at
Vanderbilt University recognized this pitfall in current prediction
models and developed a superior combined genotypic and pheno-
typic algorithm to estimate breast cancer risk. This advanced algo-
rithm takes into account cumulative estrogen exposure over a
woman’s lifetime, but additionally looks at variants in three genes
important in estrogen metabolism, COMT, CYP1A1, and CYP1B1.27
Depending on which variants in these three genes a woman has, she
can potentially skew her estrogen metabolism to produce more
DNA damaging (cancer causing) or more DNA protective (anti-can-
cer) metabolites. This cash-pay buccal swab test, called the Emetab
Estrogen Panel Breast Cancer Risk Estimate (Iverson Genetics),
therefore offers a combined calculated risk of developing breast
cancer. Since certain variants can also be protective, the test can
also identify patients who are less likely to develop breast cancer.
Knowing this information is important for any woman consider-
ing HRT. Having a high risk for the development of breast cancer
may make some women more cautious of taking HRT, whereas
other women might opt for HRT formulations with lower estrogen
profiles with increased breast cancer screening. Either way, high-
risk women may moreover want to implement lifestyle modifica-
tions such as smoking cessation and weight loss, additional services
that can be offered by the compounding pharmacist. Thus, the role
of the compounding pharmacist in providing this service can be
twofold 1) to offer the Emetab test to their patients as a service and
2) to provide personalized experiences in helping women make life-
style changes and decisions regarding their test results.
DRUG METABOLIZING ENZYME TESTING
The Emetab test is just one example of the ever-expanding
world of pharmacogenetics. Compounding pharmacists are famil-
Knowing this information is
important for any woman considering
HRT. Having a high risk for the
development of breast cancer may
make some women more cautious of
taking HRT, whereas other women
might opt for HRT formulations with
lower estrogen profiles with increased
breast cancer screening.

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Pharmacogenetics
WARFARIN TESTING
As compounding pharmacy services have
expanded to meet the growing need for spe-
cific and personalized medications and
dosages, awareness of individual genetic
differences has increased in importance in
many areas, including anticoagulation
therapy. Despite the introduction of new
anticoagulant medications, warfarin is still
widely prescribed with over 20 million pre-
scriptions written in the U.S. in 201029 and
is utilized for a variety of indications.30
Although uncommon, there may be an occa-
sion to compound warfarin for a patient
including a patient’s inability to swallow
tablets or allergy to the dye used in some
warfarin dosages.
Numerous studies have identified sig-
nificant associations of the CYP2C9 and
VKORC1 polymorphisms and individual
variability with warfarin. Individual vari-
ations in the cytochrome P450 2C9 gene
(CYP2C9) and in the vitamin K epoxide
reductase (VKOR) C1 gene (VKORC1)
have been shown to be associated with the
rate at which warfarin is metabolized and
level of sensitivity to warfarin therapy.31
While the U.S. Food and Drug Administra-
tion (FDA) has required changes to warfa-
rin labeling due to study data, the protocol
for incorporating genetic testing into war-
farin dosing remains unclear.
In an effort to quantify the impact of
incorporating pharmacogenetic informa-
tion in warfarin dosing and how it affects
patient outcomes, Iverson Genetics is
conducting a prospective, multicentered,
double-blinded, randomized, parallel-
group study to investigate if using warfa-
Excellence through Quality and Experience Resource for Compounding Pharmacies
(800) 393-1595 | www.arlok.com
DIAGRAM OF CYTOCHROME
P450 ISOENZYME 2C9 WITH
THE HEME GROUP IN THE
CENTRE OF THE ENZYME.
iar with the triad approach of one
patient, one doctor, one pharmacist.
With the vast expanse of information
coming out every day on drugs and drug-
drug interactions, it is important that
the pharmacist support this triad with
medication management knowledge.
One tool to aid in this is pharmacoge-
netic testing of the cytochrome P450
enzyme (CYO) family. The CYP are a
class of liver enzymes that metabolize
-
tions used clinically. Many SNPs have
been identified in the CYP enzymes,
although as mentioned previously, not all
SNPs have the same effect. Some SNPs
have no clinical significance and are,
therefore, of little value when genotyped.
Other SNPs may only be important in the
metabolism of one or a few drugs.
Although many companies now offer
genetic testing of enzymes involved in
drug metabolism, it is important that
pharmacists use due diligence in investi-
gating which companies test SNPs
whose information can be of clinical use.
Iverson Genetics offers a panel of CYP
enzymes called the Drug Metabolizing
Enzyme Extended panel (DMEX) that
only tests for clinically actionable vari-
ants. This means the results of this test
can be utilized to make decisions regard-
ing if a medication will work for a partic-
ular patient, and if not, if dosage
adjustments or alternative medications
could be beneficial. Such informa-
tion is additionally
useful to
avoid
ADRs.
Overall,
pharma-
coge-
netic
testing is a
service that is
not only valu-
able to the
pharmacist,
but also a
benefit to the
patient.

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Pharmacogenetics
rin-related pharmacogenetics in
calculating warfarin dose will change the
incidence of warfarin-related clinical
events (WRCE). This research, termed
the WARFARIN Study, is the only study
approved by the Centers for Medicare
and Medicaid Services (CMS) to evaluate
the value of genetic testing to improve
patient outcomes. This study will likely
determine the extreme importance of uti-
lizing genetic testing for dosing warfarin
and avoiding WRCEs and can, therefore,
be an important tool for the pharmacist
compounding warfarin.
CONCLUSION
Pharmacists must consider all factors
when dosing medication for a patient
including age, liver disease, kidney func-
tion, and weight. Until recently, however,
one key piece to this puzzle was
missing—genetics. This invisible piece of
the puzzle can now be utilized with phar-
macogenetic testing. By using pharmaco-
genetic testing, the compounding
pharmacist will be able to better predict
disease risk as well as the pharmacody-
namic and pharmacokinetic actions of
the prescriptions their patients are
taking. By targeting SNPs in the CYP
P450 family, pharmacists are able to
practice proactive versus reactive medi-
cine. Overall, pharmacogenetic testing
aims to save money due to the avoidance
of ADRs, but ultimately it is most advan-
tageous due to the long-term health ben-
efits for patients.
The ultimate goal, however, is not just
to look at how a patient’s genetics will
generally guide medication management,
but to move towards an even more per-
sonalized approach. As pharmacogenetic
testing is being used more frequently in
clinical settings, testing modalities are
moving away from simple genotyping
platforms towards more predictive
models of personalized medicine. The
Emetab Estrogen Panel is such an
example that combines a woman’s geno-
typic information with specific pheno-
typic information into a predictive model
for breast cancer risk. This information
can then be utilized to help women con-
sidering HRT make more informed deci-
sions. The algorithm used by the
WARFARIN Study31 (www.warfarindos-
ing.org) is another example of such a pre-
diction platform that uses genetic testing
combined with patient information to
predict starting dosages of a medication
that has historically been hard to control.
In summary, pharmacogenetics is poised
to become the standard of care that not
only physicians are embracing, but phar-
macists can utilize to better personalize
their patient’s needs.
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Address correspondence to Brian Fichter,
Iverson Genetic Diagnostics, Inc., 19805
North Creek Parkway, Bothell, WA 98011.
E-mail: brianf@iversongenetics.com

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