Original PDF Viewer

This embedded PDF preserves figures, tables, images, and layout.

Searchable Extracted Text

Page 1
Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacogenetic testing
in primary care
Abstract: The purpose of pharmacogenetic testing is to determine the risk of adverse reactions
and/or likelihood of a medication's effectiveness. Pharmacogenetic testing can assist primary
care providers in tailoring treatment according to a patient's genetic traits and his or her
ability to metabolize certain medication. This article will discuss the benef ts and limitations
of pharmacogenetic testing and how to interpret results.
By Julie Parve, DNP, FNP-BC; Jennifer Carlile, MSN, FNP-BC; and Josiah Parve, BS, BLS
E
ach year, more than 770,000 individuals are
filled in the US in 2013, 18% had actionable phar
injured or die from adverse drug events.1 This
macogenetics.4 Pharmacogenetic testing can prevent
number exceeds those who die from heart
adverse drug events including hospitalization and
disease, which causes approximately 630,000 deaths
death, increase approval time for drugs, and decrease
each year.2 In 2014, an estimated 1.6 million hospital
complications that may arise from delayed treatment
stays were a result of adverse drug events that started
of disease through early detection, which would im
during a hospital stay, and 1.1 million hospital stays
prove patient outcomes and patient-provider trust as
were documented for adverse drug reactions present
well as decrease healthcare costs.5
on admission, which increased significantly from 2010
Primary care providers should use pharmaco
to 2014.3 Of the approximately 4 billion prescriptions
genetic testing when standard medication regimens
Explode / Shutterstock
Keywords: adverse drug events, alleles, biomarkers, drug mechanism of action, enzymatic response, gene-drug interaction,
genetic profile, genotype, morphine milligram equivalents, pharmacogenetics, pharmacogenetic testing
44 The Nurse Practitioner -  Vol. 44, No. 10
www.tnpj.com

Page 2
Pharmacogenetic testing in primary care
are unsuccessful, adverse drug reactions are present,
After a review and an interpretation of the pharma
or misuse or diversion is suspected. This provides
cogenetic testing results, the clinic's pain management
an additional resource for primary care providers
department was notified and the patient was placed on
to personalize treatment and provide appropriate,
tapentadol and buprenorphine transdermal, both of
effective, and safe care. Evidence from systematic
which provided more effective pain relief. The patient
reviews and guidelines shows that pharmacogenetic
has been on this treatment with only small adjust-
testing is an effective method of reducing adverse
ments of dosing with a reported 80% control of pain
drug reactions.1
symptoms and higher quality of life.
 Case example #1
 Case example #2
A 51-year-old man presented to a family practice clinic
A 59-year-old woman presented to a family practice
for treatment of chronic low back pain, which he had
clinic for treatment of chronic pain secondary to bilat
suffered from for over 15 years secondary to spinal
eral knee osteoarthritis and lumbar disk degeneration
enthesopathy with reported radicular symptoms. He
with spondylosis with reported radicular symptoms.
enrolled in a pain management program but failed
She had been experiencing this pain for more than
several different pain management regimens, includ-
10 years. Referrals to pain management and ortho
ing nonsteroidal anti-inflammatory drugs (NSAIDs),
pedics in the past included failed treatments with
opioids, and skeletal muscle relaxants. He completed
NSAIDs, including celecoxib, as well as gabapentin,
physical therapy, chiropractic treatments, epidural
tramadol, hydrocodone, and acetaminophen. Addition-
injections, and lumbar radiofrequency ablation pro-
ally she had severe drug reactions to pregabalin, tizani
cedures because of the limited pain relief his medica-
dine, and cyclobenzaprine. The patient had a left total
tions provided him. At the time of his clinic visit, the
knee replacement and right knee injections, along with
patient was taking methadone 10 mg orally three times
physical therapy and epidural injections for her back
daily and oxycodone 10 mg and acetaminophen 325
pain with limited relief. At the time of her visit, she was
mg orally four times daily equaling
300 morphine milligram equivalents
(MMEs) with only 50% pain relief.6
Because of the high dosage of MMEs
and limited pain relief, the patient's
provider recommended pharmaco
genetic testing.
The patient's pharmacogenetic test results showed
taking oxycodone 10 mg and acetaminophen 325 mg
that current medications were genetically ineffective
orally twice daily and morphine 15 mg extended release
in managing his pain. For instance, methadone was
totaling an MME of 45 and her pain was reported to
found to have significant gene-drug interaction caused
be only 20% controlled with this treatment. She was
by the CYP2B6 (ultrarapid metabolizer), CYP2D6
also on duloxetine for pain and depression, provided
(intermediate metabolizer), CYP3A4 (intermediate
by her psychiatrist, though she stated this caused her
metabolizer), and CYP2D6 (intermediate metabolizer)
too much drowsiness. The FDA-approved indications
genes in this patient. This showed an inability to pre-
for duloxetine include major depressive disorder and
dict dosage adjustment because of confl icting varia-
chronic musculoskeletal pain.
tions of metabolism and genotype that may impact
The patient decided to stop all pain medications
drug metabolism, resulting in reduced effi cacy. Further,
as she was not happy with how she was feeling, and
oxycodone was found to have signifi cant gene-drug
her pain was not well controlled. She was referred
interaction with the CYP2B6 (ultrarapid metabolizer),
to a medication-assisted treatment (MAT) program
CYP3A4 (intermediate metabolizer), and CYP2D6
due to symptoms of withdrawal and was started on
(intermediate metabolizer) genes in this patient. In this
naltrexone. The patient reported limited relief with
patient, this may cause serum levels to be too high and
naltrexone and started taking more than was directed
require lower dosages, and genotype may impact drug
and was subsequently released from the program be-
mechanism of action, resulting in reduced effi cacy.
cause of medication misuse.
www.tnpj.com
The Nurse Practitioner -  October 2019 45
Pharmacogenetic testing can prevent
adverse drug events including
hospitalization and death.

Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.

Page 3
Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacogenetic testing in primary care
The patient returned to the family practice clinic
in search of other options to control her symptoms. At
that time, pharmacogenetic testing was recommended
because of the limited control of her symptoms and
suspected misuse of naltrexone.
Based on her pharmacogenetic results, duloxetine
was found to have a moderate gene-drug interaction
because of the CYP2D6 (intermediate metabolizer)
gene causing serum levels to be too high and requiring
lower dosages. She was on higher doses of duloxetine
to manage pain and depression and was likely caus
ing increased adverse reactions, such as drowsiness.
Her psychotropic testing also revealed that she was
positive for the SLC6A4 gene, showing that she has a
decreased expression of serotonin transporters that
may cause a decreased response to selective serotonin
reuptake inhibitor (SSRI) medications in general. Last,
naltrexone was found to have moderate gene-drug
interactions impacting the drug mechanism of action
and resulting in reduced efficacy. This could account
for her limited relief with higher dosages and resultant
medication misuse.
After a review and an interpretation of the patient's
pharmacogenetic testing, her psychiatrist was notifi ed
of the results, and the patient was placed on a mood
stabilizer and referred back to the MAT program and
started on sublingual buprenorphine and naloxone.
She has been stable on this treatment regimen without
adverse drug reactions and has adequate symptom
relief and improved mood.
 Testing benefits
Pharmacogenetic testing can improve patient care and
outcomes by allowing prescribers to tailor medica
tions based on a patient's genetic profi le.7 A genetic
profi le typically includes genetic variations that de
termine how individuals metabolize drugs based on
their inherited alleles, which can directly affect enzy
matic response. For example, when cytochrome P450
(CYP450) was discovered in 1955 it was found to have
a major source of variability in drug pharmacokinetics
and response.8 Since then, more biomarkers have been
discovered that are known to directly affect the rate of
drug metabolism. Currently, pharmacogenetic testing
in primary care is focused on chronic pain manage
ment and psychiatric disorders, including attention-
deficit hyperactivity disorder, but it is available for
treatment considerations in cardiology, oncology, and
gastroenterology.9
 Understanding drug metabolism and genetics
The individual-specifi c response to medication can
be attributed to multifold and complex factors, which
may be determined by individual genetic makeup.10 A
patient's ability to metabolize medications is largely
determined by his or her enzymatic response. Enzy
matic response is influenced by the type and number
of copies of alleles inherited.11 There are four basic
types of metabolizers that are scientifi cally accepted
and evaluated:
-  ultrarapid metabolizers-carry multiple copies of
functional alleles leading to excessive activity
-  extensive metabolizers-have two normal or "wild
type" alleles and have normal activity
-  intermediate metabolizers-carry one normal and
one nonfunctional or two reduced-functional alleles
and have normal or close-to-normal activity
-  poor metabolizers-carry two mutated alleles
with very limited or completely lost enzymatic
activity.12,13
Genetic polymorphisms influence the pharmaco
kinetics and pharmacodynamics of a drug response
through an individual's body. Pharmacokinetics is
the study of the absorption, distribution, metabolism,
and excretion of a drug, whereas pharmacodynamics
examines receptors, ion channels, enzymes, and the
immune system's response.14 When this informa
tion is combined, it can analyze if the drug chosen
will have little or no drug response, be too quickly
metabolized, have zero drug response at normal dose
(ultrafast metabolizer), have normal or close-to
normal drug response (extensive or intermediate
metabolizer), or have an increased drug response
from the drug being metabolized too slowly and
leading to excessive high drug levels at normal doses
and a higher chance of adverse drug reactions (poor
metabolizers).12
Drugs are metabolized in two different phases:
Phase 1 and Phase 2. Phase 1 metabolism uses chemi
cal reactions via oxidation, reduction, and hydrolysis
to result in three outcomes: drug and metabolites
become inactive, metabolites become active but are
less effective than the drug taken, or the drug taken
is not active (prodrug). Phase 2 metabolism excretes
the soluble compounds/conjugates formed in Phase
1 through urine; drugs using Phase 2 metabolism are
typically pharmacologically inactive.13 For example,
warfarin only uses Phase 2 metabolism, is excreted by
the kidneys, and is not pharmacologically active.12,15
46 The Nurse Practitioner -  Vol. 44, No. 10
www.tnpj.com

Page 4
Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.
Because drugs break down into separate metabo
lites when being metabolized by the body, there are
multiple alleles that infl uence cytochromes and can
affect a drug's metabolism. For example, morphine
is broken down into three metabolites: its nonactive
form (normorphine), its active metabolite (identical
to the pharmaceutical opioid hydromorphone), and its
active metabolites that are not pharmaceutical opioids
(Morphone-3-G glucuronide and Morphone-6-G
glucuronide).16 Each category of metabolites can vary
based on each drug's pharmacokinetics and pharma
codynamics, even within a drug class and its respective
targets. For example, a drug that does not have active
metabolites, such as methadone, instead has several
inactive metabolites and induces its analgesic response
through its affinity for the N-methyl-d-aspartate re
ceptors. Although there is not an active metabolite, the
intermediate products that are produced can either
be toxic or have clinical usefulness.13 It is important
to have a detailed understanding of each drug and its
pharmacokinetic and pharmacodynamic properties
and how they are used by pharmacogenetic databases
to properly and effi ciently produce safe prescribing
guidelines.15
 Pharmacogenetics and drug labeling
More than 70 FDA-approved US drugs contain phar
macogenetics information (biomarkers) on their
label.17 These include commonly prescribed drugs,
such as amitriptyline (CYP2D6), celecoxib (CYP2D6),
citalopram (CYP2C19), escitalopram (CYP2D6 and
CYP2C19), metoprolol (CYP2D6), omeprazole (CY
P2C19), rosuvastatin (SLCO1B1), sulfamethoxazole
and trimethoprim (G6PD), tramadol (CYP2D6), and
warfarin (CYP2C9 and VKORC1). Drug labeling can
describe:18
-  drug exposure and clinical response variability
-  risk of adverse reactions
-  genotype-specifi c dosing
-  mechanisms of drug action
-  polymorphic drug target and disposition genes
-  trial design features.
 Clinical trials
There are many studies related to pharmacogenetics
and patient outcomes in primary care, and several
large clinical trials are in process. The authors found
more than 340 clinical trials involving pharmacogenet
ics that were recently completed and an additional 300
Pharmacogenetic testing in primary care
that were in process or recruiting patients worldwide
at the time of this article's publication. Perez and col
leagues conducted a randomized, double-blind study
of 280 patients with major depressive disorder over a
12-week period of time in Europe.19 Results showed a
significant improvement of response in the pharma
cogenetics treatment group versus the control group,
but the results were more statistically significant in the
patients who had failed on more than one medication
before the trial started and they experienced signifi 
cantly fewer adverse reactions.
Based on a 2017 study of 134 patients with non
cancerous pain, after review of genetic testing results,
physicians adjusted treatment plans for 40% of pa
tients. When medication changes were made, there
were fewer adverse drug reactions based on the genetic
testing results, and a statistically signifi cant 72% of
patients showed improvement in clinical status.12
Lerman and colleagues conducted a study with
1,246 participants that used nicotine metabolite ra
tio as a genetically informed biomarker response to
smoking cessation treatment. The study determined
that treating normal metabolizers with varenicline
and slow metabolizers with nicotine patch optimized
quit rates and minimized adverse reactions for all
smokers.16
The Clinical Pharmacogenetics Implementation
Consortium has guidelines designed to help clinicians
understand how available genetic test results should
be used to optimize drug therapy, rather than whether
tests should be ordered.18 They include guidelines for
clopidogrel therapy, phenytoin dosing, and dosing
of SSRIs, to name a few. This is a great resource for
clinicians.
 Current use in primary care
It is estimated that 50% of all opioid prescriptions are
written by primary care providers and that pain con
trol is one of the most common reason that patients
visit their healthcare provider.18,19 According to a 2018
CDC report, an estimated 50 million individuals in
the US have chronic pain.4 Not all patients respond
to pain medication the same way, and there is a high
potential for abuse, misuse, and addiction. Pharmaco
genetic testing can predict the individual response to
drug therapy either before therapy is initiated or when
mainstream therapies are not effective in chronic pain
management.20 The use of evidence-based guidelines
when prescribing medication and treating diseases
www.tnpj.com
The Nurse Practitioner -  October 2019 47

Page 5
Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacogenetic testing in primary care
is recommended, but many times prescribers rely on
trial-and-error, which may cause patients to undergo
undue stress, time off work, and many unnecessary of
fice visits. Not only can pharmacogenetic testing assist
in the treatment of patients and their responses to pain
medications, it can also help reduce adverse reactions.
Genetics can explain the variability of responses, and
testing can predict more effective medication choices
and doses.21
For example, current guidelines recommend using
standard urine drug screens (UDSs) to determine pa
tient adherence to controlled medication regimens.20
When inconsistencies occur, typically the patient-
provider relationship is terminated or controlled sub
stances are discontinued because of suspected misuse
or diversion. However, drug metabolism may differ
between patients and may affect drug metabolites ana
lyzed in standard UDSs.22,23 In their 2018 publication,
Crist and colleagues provide a detailed chart about
genetic variation associated with opioid use disorder
and how it affects UDS results.24
 Barriers
In November 2017, the American Medical Association
voted to advance the development of a comprehen
sive strategy that allows more consistent coverage of
genomics and genetic tests and accessibility.24 Barriers
may include limited provider knowledge in ordering
and interpreting pharmacogenetic testing results and
its benefits, including current research supporting its
use.21 Health insurance policies may not cover pharma
cogenetic testing for all patients, and pharmacogenetic
companies often use different methods for report
ing results, which make the application of clinical
decision-making challenging.
Other barriers include patient concerns about ge
netic testing, which include consent, confi dentiality,
and inequality in healthcare.21 Ethical implications
include genetic discrimination and the use of genetic
information in research.25 In 2008, Congress passed the
Genetic Information Nondiscrimination Act (GINA)
Gene-drug interaction resources
The Drug Gene Interaction Database
www.dgidb.org
The FDA Table of Pharmacogenetic Biomarkers in
Drug Labeling
www.fda.gov/drugs/science-research-drugs/table
pharmacogenomic-biomarkers-drug-labeling
to protect Americans from genetic discrimination.
This Act prevents insurance companies from using that
information to adjust premiums and deny coverage for
preexisting conditions and employers from denying
employment based on genetic testing. GINA does not
apply to life insurance, disability or long-term care
insurance, or care provided in the military, Veterans
Affairs, or the Indian Health Service.12 Additionally,
patients may confuse pharmacogenetic testing with ge
netic variant trait testing and may be resistant to testing
if they believe it can affect coverage by their insurance
carrier for a potential preexisting condition.12
 Conclusion
In the rapidly advancing medical field, it is important
for every healthcare practitioner to have a basic under
standing of pharmacogenetic testing, when it should
be used, and its benefits and limitations. This emerg
ing science may give future practitioners the ability to
lessen adverse drug reactions and reduce deaths and
hospitalizations caused by drug interactions. Resources
are available online to help clinicians calculate gene-
drug interactions. (See Gene-drug interaction resources.)
A patient given a chance to experience fewer adverse
reactions, allowing for fewer errors in prescribing med
ications, could lead to more successful and prompt
treatments in short- and long-term diseases. There is
still more detailed research warranted, including larger,
more diverse cohorts for a better understanding of how
pharmacogenetic testing can be best used in primary
care. NPs should not avoid using newer technology
as long as they understand the potential benefi ts and
limitations. Relying solely on pharmacogenetic testing
for treatment in primary care is not recommended.
REFERENCES
1. Sonawane KB, Cheng N, Hansen RA. Serious adverse drug events reported
to the FDA: analysis of the FDA Adverse Event Reporting System 2006-2014
Database. J Manag Care Spec Pharm. 2018;24(7):682-690.
2. Murphy SL, Xu J, Kochanek KD, Arias E. Mortality in the United States,
2017. NCHS Data Brief, no 328. Hyattsville, MD: National Center for
Health Statistics; 2018.
3. Weiss AJ, Freeman WJ, Heslin KC, Barrett ML. Adverse Drug Events in U.S.
Hospitals, 2010 Versus 2014. Agency for Healthcare Research and Quality.
Healthcare cost and utilization project. 2018.
4. Sharma M, Kantorovich S, Lee C, et al. An observational study of the impact
of genetic testing for pain perception in the clinical management of chronic
non-cancer pain. J Psychiatr Res. 2017;89:65-72.
5. Elliott LS, Henderson JC, Neradilek MB, Moyer NA, Ashcraft KC, Thiru
maran RK. Clinical impact of pharmacogenetic profiling with a clinical
decision support tool in polypharmacy home health patients: a prospective
pilot randomized controlled trial. PLoS One. 2017;12(2):e0170905.
6. Centers for Disease Control and Prevention. Calculating total daily dose of
opioids for safer dosage. www.cdc.gov/drugoverdose/pdf/calculating_
total_daily_dose-a.pdf.
48 The Nurse Practitioner -  Vol. 44, No. 10
www.tnpj.com

Page 6
Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacogenetic testing in primary care
19. Perez V, Salavert A, Espadaler J, et al. Efficacy of prospective pharmaco-
genetic testing in the treatment of major depressive disorder: results of a
randomized, double-blind clinical trial. BMC Psychiatry. 2017;17(1):250.
20. Lerman C, Schnoll RA, Hawk LW Jr, et al. Use of the nicotine metabolite
ratio as a genetically informed biomarker of response to nicotine patch or
varenicline for smoking cessation: a randomised, double-blind placebo-
controlled trial. Lancet Respir Med. 2015;3(2):131-138.
21. Verbelen M, Weale ME, Lewis CM. Cost-effectiveness of pharmacogenetic-
guided treatment: are we there yet? Pharmacogenomics J. 2017;17(5):395-402.
22. King SA. Chronic pain in primary care: practice update. 2016. www.patient-
careonline.com/special-report/chronic-pain-primary-care-practice-update.
23. Centers for Disease Control and Prevention. Why guidelines for primary care
providers? www.cdc.gov/drugoverdose/pdf/guideline_infographic-a.pdf.
24. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-
Impact Chronic Pain Among Adults-United States, 2016. MMWR Morb
Mortal Wkly Rep. 2018;67(36):1001-1006.
25. AACC.org. CDC's new opioid guidelines. 2016. www.aacc.org/publications/
cln/cln-stat/2016/april/21/cdcs-new-opioid-guidelines.
Julie Parve is an associate professor at Concordia University, Mequon, Wis., and
an FNP at Froedtert Community Physicians, Kewaskum, Wis.
Jennifer Carlile is an FNP at MHC Healthcare, Marana, Ariz.
Josiah Parve is a graduate of University of Wisconsin-Milwaukee, Milwaukee, Wis.
The authors have disclosed no financial relationships related to this article.
DOI-10.1097/01.NPR.0000580780.66980.85
7. Mills RA, Eichmeyer JN, Williams LM, et al. Patient care situations benefi t
ing from pharmacogenomic testing. Curr Genet Med Rep. 2018;6:43.
8. Dawes M, Aloise MN, Ang JS, et al. Introducing pharmacogenetic testing
with clinical decision support into primary care: a feasibility study.
CMAJ Open. 2016;4(3):E528-E534.
9. Damani SB, Topol EJ. Emerging clinical application in cardiovascular phar
macogenomics. Wiley Interdiscpl Rev Syst Biol Med. 2011;3(2):206-215.
10. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism:
regulation of gene expression, enzyme activities, and impact of genetic
variation. Pharmacol Ther. 2013;138(1):103-141.
11. Abubakar A, Bentley O. Precision medicine and pharmacogenomics in com
munity and primary care settings. Pharm Today. 2018;24(2):55-68.
12. Ahmed S, Zhou Z, Zhou J, Chen SQ. Pharmacogenomics of drug metaboliz
ing enzymes and transporters: relevance to precision medicine. Genomics
Proteomics Bioinformatics. 2016;14(5):298-313.
13. Richeimer S, Lee JJ. Genetic testing in pain medicine-the future is coming.
Pract Pain Manage. 2017;16(8).
14. Farinde A. Overview of Pharmacodynamics-Clinical Pharmacology. Merck
Manuals Professional Edition, Merck Manuals. 2019. www.merckmanuals.
com/professional/clinical-pharmacology/pharmacodynamics/overview-of
pharmacodynamics.
15. Patel S, Patel N, Preuss C. Warfarin. StatPearls. U.S. National Library of
Medicine. 2019.
16. Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613-624.
17. Marte F, Cassagnol M. Enalaprilat. StatPearls, St. John's University. 2019.
18. U.S. Food and Drug Administration. Table of pharmacogenomic biomarkers
in drug labeling. 2019. www.fda.gov/drugs/science-research-drugs/table
pharmacogenomic-biomarkers-drug-labeling.
www.tnpj.com
The Nurse Practitioner -  October 2019 49