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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2593_Библиотеки_им_академика_М_И_Перельмана
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QUESTION 1: H.T. is a 12-year-old female who had an operation resulting in the
development of malignant hyperthermia (MH). Following recovery, she is found
to have a pathogenic SNP variant (mutation) at the 7300 nucleotide (referred to
as c.7300G>A) in the RYR1 gene, a common variant associated with
predisposition to MH. H.T.’s providers discuss the influence of this finding on her
future medical and drug management.
What additional clinical considerations should her providers address following
H.T.’s genetic findings and presentation?
Genes are inherited, so any discussion relating to clinically
significant genetic variants should also include raising awareness of
the variant’s implications beyond the patient who was tested. In the
case of H.T., the mutation associated with MH is dominant, the
clinical consequence can be life-threatening, and the likelihood of
inheritance is high. Counseling and testing of parents and extended
family members could therefore be recommended. When an
individual is being counseled on pharmacogenomic testing results
before any related incident, it is important to raise the possibility that
the results could have implications for the greater family.
73
MAKING THE CASE FOR
PHARMACOGENOMICS
In general, several studies have shown that patients are more
adherent with their medication regimes after receiving personalized
genotyping results, even if the findings show “normal” enzyme
function.74 Because medication adherence is an ongoing challenge
in optimizing patient care, pharmacogenomic testing could offer a
potential incentive.
An increased understanding of pharmacogenomics has also
allowed pharmaceutical companies to design and develop drugs that
specifically target protein changes associated with certain mutations,
making regimens more personalized and effective. To determine
whether a patient will benefit from these targeted therapies,
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companion tests (pharmacogenetic assays that target the variants of
interest) are usually required. A pharmacist must understand which
medications require companion testing and know how to interpret
and apply the associated results. Possible hurdles for companion
testing requirements by drug manufacturers may include the
potential wait time in getting insurance approval for the companion
test that could delay care.
CASE 4-11
QUESTION 1: K.D. is a 22-year-old female with cystic fibrosis. Her pulmonologist
is interested in prescribing the drug ivacaftor. K.D. comes to the pharmacy and
mentions the need for a special test before starting this new treatment, but she
cannot remember why the test is necessary.
What test is K.D. likely getting to determine whether she is eligible to receive
ivacaftor?
Ivacaftor (Kalydeco®) is a drug used to treat cystic fibrosis, and it
acts at the cystic fibrosis transmembrane conductance regulator
(CFTR) channel. CFTR protein is found on a variety of tissue
surfaces, including the lungs. When functioning properly, the CFTR
protein is a key component in maintaining intracellular salt balance.
75
Cystic fibrosis results from a variety of possible genetic mutations,
causing dysfunctional CFTR protein and leading to fluid imbalances,
the buildup of secretions, and several related complications.
Kalydeco® is an oral agent approved for patients with cystic
fibrosis carrying 10 specific variants in the CFTR gene: G551D,
G1244E, G1349D, G178R, G551S, R117H, S1251N, S1255P,
S549N, and S549R. For this subset of patients, the drug acts as a
CFTR potentiator, increasing CFTR activity, restoring electrolyte
balance, reducing the buildup of secretions, and improving health
outcomes, such as pulmonary function and weight gain for affected
patients.76 For patients with cystic fibrosis affected by other
mutations, the drug will be ineffective. K.D.’s doctor likely ordered a
genetic test to determine which mutation was the cause of her cystic
fibrosis diagnosis.
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Ivacaftor was approved in 2012 for patients with the G551D
mutation, offering promise for continued future development of
therapies targeting the underlying causes of genetic diseases. This
promise remains encouraging because the use of ivacaftor has since
been approved in the treatment of several additional gene mutations.
In addition, new similar targeted therapies such as lumacaftor
(Orkambi™), a CFTR corrector, and combination products such as
elexacaftor/tezacaftor/ivacaftor (Trikafta™) continue to enter the
market.
77
Another potential use of pharmacogenomics involves salvaging
drugs with high toxicity profiles. Historically, many 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 patients should avoid use.
Despite the many advances in testing and clinical application,
preemptive pharmacogenomic testing before the development of an
adverse effect or lack of response is not currently widely used, for
several reasons. A major barrier comes from the fact that health care
professionals, including pharmacists, lack the knowledge necessary
to apply pharmacogenomic data. One recent study found that only
29% of the physicians surveyed received any formal education
around pharmacogenomics, and only 10.3% felt knowledgeable
enough to prescribe or discuss the results of pharmacogenomic
testing.78 Another large impediment to implementation is the lack of
consistent reimbursement policies by insurance providers. To
achieve widespread and consistent pharmacogenomic testing
coverage by insurance companies, there is a need for concerted
regulatory efforts and continued proof that pharmacogenomic testing
improves outcome and decreases cost.
2,15,79
At this time, the majority of preemptive pharmacogenomic testing
is happening in places where there is institutional support of targeted
program development, such as academic medical and cancer
centers, or where programs can directly bill patients for services not
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covered by insurance, as is seen with for-profit pharmacogenomic
testing companies.
CASE 4-11, QUESTION 2: What references could be used to assist pharmacists
and providers in interpreting pharmacogenomic results and applying any variant
findings to subsequent drug dosing decisions?
The FDA and European Medicines Agency (EMA) currently list
pharmacogenomic markers in 326 and 78 drug labels,
respectively.
80,81
To be included in the FDA labeling, a
pharmacogenomic marker must have known clinical consequence,
such as an increase in adverse effects or reduction in efficacy, or
actionable recommendations for alternative treatment or dose
modification. In addition, as referenced earlier, PharmGKB, CPIC,
and DPWG provide a valuable and accessible resource for
pharmacists.
Incorporating pharmacogenomic data into electronic medical
record systems is challenging. Result reports from laboratories
capable of running these tests are rarely in a machine-readable
format and are generally delivered as PDF documents to be scanned
into a patient’s chart.82 This scenario presents a major systemic
challenge in being able to provide relevant pharmacogenomic data
at the time they are most needed, during the drug prescribing and
dispensing processes. Pharmacogenomic results remain relevant
throughout a person’s lifetime and require significant bioinformatics
expertise to house, retrieve, interpret, and present to the end user at
the right time.83 To ensure that the most recent variant knowledge is
being applied, it is also important to track the evolution of testing
options over time. It is possible that updated analyses could be
needed, such as sequencing a new sample or reprocessing a
previous sample with new algorithms. A payment model for
reinterpretation without retesting is extremely uncommon in the field
of laboratory medicine today.
Other extremely important considerations around housing, storing,
and using pharmacogenomic data include security and privacy. Data
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security refers to protection of information from breaches and
inadvertent dissemination, whereas data privacy relates to
respecting patient preferences for data sharing, both with the patient
directly as well as with the larger health care community. The recent
European Union (EU) implementation of the General Data Protection
Regulation (GDPR) is of particular interest in this realm given its
focus on digital data (https://gdpr-info.eu/ [accessed February 15,
2022]). The GDPR was designed to ensure that personal data are
gathered legally and under strict conditions. In addition, those who
collect and manage personal data are obliged to protect it from
misuse and exploitation, as well as to respect the rights of data
owners with reach beyond the EU.
Ultimately, how is the decision made to offer and incorporate
pharmacogenomic testing into practice? In a nonideal scenario,
health care providers have no choice when patients hand them a
printed report from direct-to-consumer pharmacogenetic testing
services. These patients look to their health care team to consider
the results when prescribing and dispensing decisions are made,
making pharmacogenomic knowledge critical. Academic medical
programs have begun to incorporate pharmacogenomic science into
core curricula, but it is often in the form of a single 1- to 2-hour
lecture. This level of training will be inadequate in preparing
providers to deal with the era of personalized medicine and the
eventual day when everyone will have access to their own genomic
data.
When assessing the value of incorporating pharmacogenomic
testing into practice, several factors impact the return on investment
and influence on clinical outcomes. These factors include, but are
not limited to, the number of patients needed to be tested to find one
patient with an actionable variant, ethnic variation given that
populations are now blended and clear ancestry knowledge is often
lacking, the cost of testing, the likelihood of insurance
reimbursement, and the cost savings offset by averting serious
adverse reactions or nonresponse.
79
Genetic testing can also introduce challenging ethical questions,
particularly when dealing with broader tests covering large sections
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of DNA such as whole-exome or whole-genome sequencing.
Although most people want to know whether they should take a
medication, many do not wish to know their risk of developing
Alzheimer disease or breast cancer. The American College of
Medical Genetics (ACMG) updated a position statement relating to
this topic in 2021, listing a total of 73 genes with pathogenic variants
causing specific defined diseases when tested, irrespective of the
age of the patient.84 However, consent should be obtained to fully
inform the patient and/or their parent(s)/legal guardian(s) of the
implications, including with respect to the risks to them and their
relatives of developing the disorders and the potential for insurance
discrimination based on pathogenic findings.
85,86
Although the 2008
Genetic Information Nondiscrimination Act (GINA) makes it illegal for
health insurance coverage to be denied because of genetic findings,
there is no protection for life or long-term care insurance coverage.
87
CONCLUSION
Pharmacogenomics is simultaneously an exciting and a challenging
component of personalized medicine and the practice of pharmacy.
One of the most important points to remember when working with
pharmacogenomic data is that they serve as an additional clinical
marker but are 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
metabolism in younger pediatric patients.
Pharmacists are uniquely qualified to interpret and apply
pharmacogenetic findings to medication selection and dosing
decisions. To adequately fulfill this role in a clinical setting,
pharmacists need focused education on the topic of
pharmacogenomics, understanding of how to apply validated
algorithms, access to continually updated literature, and a
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partnership with genetic experts, including geneticists and genetic
counselors.88 This chapter has only briefly touched upon examples
of actionable pharmacogenes. The following key references and
websites provide extensive information for further study.
KEY REFERENCES AND WEBSITES
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT12e. Given here are the key references
and websites for this chapter, with the corresponding reference
number in this chapter found in parentheses after the reference.
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doi:10.1007/s40291-013-0028-5 (7)
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The All of Us Research Program (formerly named the Precision Medicine Initiative
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PharmGKB.org, http://www.pharmgkb.org
Warfarin dosing, http://www.warfarindosing.org/Source/Home.aspx
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