The lack of response demonstrated by P.F. to the standard dose of paroxetine fits
the phenotype of an ultrarapid metabolizer. The recommendation per the CPIC
guideline would be to choose another drug not primarily metabolized via the
47 This case provides a prime example of how time can be wasted
and patient morbidity increased due to lack of response when pharmacogenomic
markers are not considered prior to initiating therapy.
from the formulary. What genotype is correlated with the risk of life-threatening apnea?
Codeine is metabolized by CYP2D6 to the active metabolite morphine, which
provides analgesic properties. For patients with the ultrarapid metabolizer status
described earlier, the amount of morphine generated can exceed the body’s ability to
convert to less toxic metabolites, resulting in life-threatening apnea.
metabolizer phenotype is found in up to 4% of the population.
several loss-of-function variants with far-ranging incidence across ethnicities. For
example, the *4 allele is found in 6% of African-Americans, 5% of Asians, and up to
18% of European-Americans/Europeans.
50 These variants confer little to no enzyme
function, resulting in lack of morphine formation. Patients with these genotypes will
not have the desired analgesic response to codeine.
voriconazole dose for this baby?
Voriconazole is metabolized by CYP3A4, CYP2C9, and CYP2C19, with the most
significant contribution coming from CYP2C19.
Association has guidelines in place recommending monitoring of voriconazole serum
concentrations for CYP2C19 poor and intermediate metabolizers, as these patients
have been found to have higher concentrations of active drug and increased risk of
toxicity. The consideration for a person with the CYP2C19 *17/*17 is the potential
for increased breakdown of active drug and treatment failure.
Given this patient’s age, there are multiple complex factors that need to be
considered for dosing, both genetic and nongenetic. As voriconazole is dosed by
body weight, the actual body weight of the child is necessary for an appropriate dose
52 Drug–drug interactions may also need to be considered in the event that
the patient is receiving medications that induce or inhibit enzymes in the drug’s
pathway. Other variables also contributing to complicated infant dosing and
clearance unpredictability include developing gastrointestinal and renal function and
fluctuations in body fat and water composition affecting volume of drug
53 Additionally, although the patient’s genotype suggests that she will
have increased breakdown of the active drug, it is known that regardless of genotype,
humans are not born with fully functional CYP enzymes.
CYP enzyme development occurs at variable rates over time making it difficult to
determine the contribution of pharmacogenomic variants on optimal dosing (see Fig.
4-3). An excellent summary review of enzyme maturation by Kearns and colleagues
was published in the NEJM in 2003.
53 CYP1A2, for example, is virtually
undetectable at birth, with initial development of low-level enzyme concentrations
54,55Although general trends are observed, it is also understood that among
individuals, development rates vary throughout childhood, particularly in the first
54 Given this consideration, pharmacogenomics in the infant population
may be less of reliable factor than it is in adults, and its overall contribution remains
unpredictable as few studies are dedicated to the effects of pharmacogenomic
variants in younger individuals. Therefore, it is particularly important in children and
infants to monitor for drug concentrations, response, and toxicities, and to adjust dose
55 Voriconazole is of particular concern with this group, with evidence
suggesting that current pediatric dosing recommendations may lead to subtherapeutic
concentrations and a general increased risk of treatment failure.
Figure 4-3 CYP2C19 enzyme activity by age.
management, what else would be important to discuss?
Genes are inherited; therefore, any discussion of genetic variants must be
undertaken with an awareness of the greater implications of any identified changes. In
this case especially, because the consequences of the gene change are so profound
and the mutation is a dominant one, it is likely that she inherited the change. An
exploration of the family history may suggest that one parent is more likely to be the
carrier than another, and counseling with a view toward testing may well be guided
by such information. Furthermore, one must consider the potential for siblings,
grandparents, and the extended family to be affected depending on the severity of the
variant status and the clinical picture.
In the situation where the individual is being counseled for pharmacogenomic
testing presymptomatically, it is important to raise the possibility that the results may
have implications for the greater family before testing is undertaken.
MAKING THE CASE FOR PHARMACOGENETICS
Pharmacogenomics has allowed pharmaceutical companies to design and develop
drugs specifically targeted at certain mutations. In order to determine the right patient
for the drug, companion tests (pharmacogenetic assays that target the variants of
interest) are usually required. The pharmacist must understand which medications
require companion testing and be able to interpret the results. Although up to 50% of
drug companies are pursuing drug targets that would require companion genetic tests,
there are several hindrances that must be addressed, including potential delays in
companion test approval and potentially decreasing the patient base by eliminating
those who would otherwise be prescribed the drug in the absence of knowledge of
2 Additionally, several studies have shown that patients
are more adherent with their medications after having personalized genotyping, even
if the results show “normal” enzyme function.
variants qualify for ivacaftor therapy?
Ivacaftor (Kalydeco) is a drug for cystic fibrosis that targets ten specific variants
in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. If a patient has a
variant status other than G551D, G1244E, G1349D, G178R, G551S, R117H,
S1251N, S1255P, S549N, or S549R, the drug will be ineffective.
The CFTR gene codes for the CFTR protein on a variety of tissue surfaces,
including the lungs. When functioning properly, the CFTR protein is a key component
in maintaining intracellular salt balance.
In cystic fibrosis, because of a variety of
possible genetic mutations the CFTR protein fails to function properly leading to
fluid imbalances, the buildup of secretions, and several related complications.
Ivacaftor acts as a CFTR potentiator increasing chloride ion transport, restoring
electrolyte balance, reducing the buildup of secretions, and improving health
outcomes such as pulmonary function and weight gain for affected patients.
approval of this drug in 2012 for patients with the G551D mutation offered promise
for continued future development of therapies targeting causes of disease that are
genetically associated. This promise remains encouraging as the use of ivacaftor has
since been approved in the treatment of several additional gene mutations, and new
similar targeted therapies such as lumacaftor (Orkambi), a CFTR corrector, continue
Another potential use of pharmacogenomics involves salvaging drugs with high
toxicity profiles. Historically, drugs have been taken off the market after an
unacceptable number of patients either suffered significant morbidity or mortality
secondary to the use of the drug. In some cases, pharmacogenomic studies may be
able to determine which patients could continue to benefit from the drug and which
for patients’ use must be avoided.
Despite all of the advances in testing and application, pharmacogenomic
preemptive testing (testing prior to the development of an adverse effect or lack of
response) is not currently in wide use. There are several reasons for this. The lack of
knowledge by healthcare professionals, including pharmacists, is a large barrier. One
recent study demonstrated that only 29% of the physicians surveyed had received any
formal education and only 10.3% felt knowledgeable enough to prescribe or discuss
the results of pharmacogenomic testing.
64 Another large impediment to
implementation is the lack of consistent reimbursement by insurance providers.
Consistent coverage by insurance companies will require regulatory effort and
additional proof that pharmacogenomic testing improves outcome and decreases
Therefore, at this time, the majority of preemptive testing is being done in
academic medical centers, in cancer centers, or by for-profit pharmacogenomic
testing companies that can either institutionally support the development of the
programs or can directly bill for the services not covered by insurance.
CASE 4-11, QUESTION 2: What references could be used to assist in interpretation of pharmacogenomic
markers and subsequent drug dosing recommendations?
Currently, the FDA lists pharmacogenomic markers in 190 drug labels and the
European Medicines Agency lists pharmacogenomic information in 78 drug
In order to be included in the FDA labeling, the pharmacogenomic marker
must have actionable data, such as an increase in adverse effects or reduction in
in patients with certain variants. Guidelines for drug dosing and selection have
been developed by the Clinical Pharmacogenomics Implementation Consortium
(CPIC) and the Pharmacogenetics Working Groups of the Royal Dutch Pharmacists
Association (DPWG). Each guideline is rated on the level of evidence available to
support the recommendation. Currently, there are 36 CPIC Level I evidence
published guidelines available on www.pharmgkb.org, a website supported by the
NIH and hosted by Stanford University.
67 The site houses a wealth of information
including pathway diagrams, annotated bibliographies, and lookup tables. It is
important to note, the guidelines do not address who should be tested, but instead
focus on what to do with the data if it is available.
Incorporating pharmacogenomic data into the electronic medical record systems
used by many hospitals, clinics, pharmacies, and primary care offices is challenging
at best. Result reports from the laboratories capable of running these tests are rarely
in a machine-readable format and are generally scanned as pdf documents to the
68 This becomes a major challenge for the system to be able to
provide relevant pharmacogenomic data at the time it is needed, usually during
prescribing of a drug. Results of this type that persist throughout a person’s lifetime
and are relevant all along the continuum require significant bioinformatics expertise
to house, retrieve, interpret, and present to the end user at the right time.
Additionally, understanding that the testing will evolve over time, either resulting in
the need to sequence a new sample or ideally, reanalyzing the previously deep
sequenced sample with new algorithms to apply the most recent variant knowledge.
A payment model for reinterpretation without retesting is extremely uncommon in the
field of laboratory medicine today.
Another extremely important consideration is data security and privacy. Data
security refers to the ability to protect information from breaches and inadvertent
dissemination. Data privacy refers to the ability to respect patient preference for data
sharing, both with the patient themselves and with the larger health care community.
How is the decision made to offer and incorporate pharmacogenomic testing into
practice? In some cases, it becomes forced upon the healthcare provider, such as a
pharmacist or primary care physician, who is handed a printed report by a patient
who has purchased direct to consumer pharmacogenetic testing services and insists
that the information be considered when prescribing and dispensing decisions are
made. Clearly, that is a less than ideal situation. Healthcare provider education has
begun to incorporate pharmacogenomic science into the core curriculums, but it is
often in the form of a single1-to 2-hour lecture. This will be inadequate preparation
to deal with the era of personalized medicine and the eventual day when everyone
will have access to their own genomic data.
When assessing a pharmacogenomic test for potential incorporation into practice,
several factors impact the return on investment and clinical outcome. These include
but are not limited to the number of patients needed to be tested in order to find one
patient with an actionable variant (also known as the incidence of variant status) and
the ethnic variation, being cognizant that we are becoming a very blended population
without full knowledge of our entire ancestry. Additionally, institutions must
investigate how much each test costs to run, if it will be reimbursed, and what are the
cost savings offset by averting serious adverse reactions or the consequences of
Genetic testing can introduce ethical questions that can be challenging, particularly
when dealing with sequencing large portions of the DNA. Although most people want
to know whether or not they should take a medication, many do not wish to know
their risk of developing Alzheimer disease or breast cancer. This becomes a concern
with some of the broader sequencing tests such as whole exome or whole genome.
The American College of Medical Genetics and Genomics (ACMG) released a
position statement in 2013, recommending mandatory reporting in 24 categories of
diseases caused by genetic variants whenever a sequencing test is performed,
regardless of patient preference around wanting to know that information and
irrespective of age of the patient.
72 Arguments against this practice have included the
patient’s right to decide, informing the parents/caregivers of an adult-onset disease
for a child, and insurance discrimination risks.
73,74 Although it is illegal for health
insurance coverage to be denied due to genetic findings following the passage of the
Genetic Information Nondiscrimination Act (GINA) in 2008, this is currently not true
for life or long-term care insurance coverage.
Pharmacogenomics is simultaneously an exciting and challenging component of
personalized medicine and the practice of pharmacy. One of the most important
points to remember is that pharmacogenomic information is an additional clinical
marker, but is rarely the only answer. A patient’s organ function, disease state, diet,
smoking status, other environmental factors, and drug–drug interactions play a very
large role in the disposition of drugs. Age-based maturation of enzyme function must
also be accounted for when determining the impact of the genotype on drug
Pharmacists are uniquely qualified to interpret and apply pharmacogenetic findings
to medication recommendations. However, this will require adequate preparation,
application of validated algorithms, access to continually updated literature, and a
partnership with genetic experts, including geneticists and genetic counselors.
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
EnglJ Med. 2003;349:1157–1167. (53)
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/default.htm.
NIH Precision Medicine Initiative. http://www.nih.gov/precisionmedicine/.
PharmGKB.org. http://www.pharmgkb.org.
Warfarin Dosing. http://www.warfarindosing.org/Source/Home.aspx.
PHARMACOGENOMICS AND PERSONALIZED MEDICINE
Shabaruddin FH et al. Economic evaluations of personalized medicine: existing challenges and current
developments. Pharmacogenomics Pers Med. 2015;8:115–126.
Scott S. Personalizing medicine with clinical pharmacogenetics. Genet Med. 2011;13(12):987–995.
Motulsky AG. Drug reaction enzymes and biochemical genetics. J Am Med Assoc. 1957;165:835–837.
Acad Emerg Med. 2005;12(12):1227–1235.
Med Assoc. 2011;306(11):1252–1253.
Lexicomp. Isoniazid. Copyright 1978–2015. Hudson, OH: Lexicomp. Accessed September 8, 2015.
Daly AK. Drug-induced liver injury: past, present and future. Pharmacogenomics. 2010;11(5):607–611.
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