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CoA Reductase Inhibitors
SLCO1B1
rs4149056
Genotype
Myopathy
Risk With
Simvastatin
Use Simvastatin Dosing Recommendation
TT Normal Prescribe standard starting dose and modify based
on tolerance and disease response.
TC Intermediate Prescribe a lower dose or consider alternative statin
(such as pravastatin or rosuvastatin). Routine
monitoring of CK may be considered.
CC High Prescribe a lower dose or consider alternative statin
(such as pravastatin or rosuvastatin). Routine
monitoring of CK may be considered.
CK, creatine kinase; HMG-CoA, β-hydroxy-β-methylglutaryl-coenzyme A.
Source: Adapted from Ramsey LB, Johnson SG, Caudle KE, et al. The clinical
pharmacogenetics implementation consortium guideline for SLCO1B1 and
simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther.
2014;96(4):423–428. © 2014 American Society for Clinical Pharmacology and
Therapeutics. Reprinted by permission of John Wiley & Sons, Inc.
NONMETABOLIC IMPLICATIONS
CASE 4-6
QUESTION 1: J.C. is an 18-year-old female with a past medical history of
epilepsy. Following a failed course of levetiracetam, her physician has decided
to start her on carbamazepine therapy for seizure control. Approximately 2
months after starting the drug, J.C. has been seizure free but started feeling flulike symptoms with a headache and fever. She also noticed that her skin was
becoming red and itchy in several locations. The rash quickly progressed to the
point where she notes swelling and the formation of blisters on her nostrils,
eyes, and lips. J.C. then realized that she might be experiencing something
more than a common rash and called the pharmacy in a panic to ask if it was
possible that she is reacting to her medication, even though she had been on it
for some time.
Given the known side effects of carbamazepine, is it possible that J.C. is
experiencing a drug reaction?
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ADRs are often thought to happen soon after initial doses of
medication. However, delayed hypersensitivity is also possible. In
the case of carbamazepine, these reactions are linked to DNA
changes within the human leukocyte antigen (HLA) genes. There is
a strong association between positive HLA-B*1502 gene variant
carrier status and increased risk of severe cutaneous adverse
reactions.47 A less-established link has also been seen with carriers
of the HLA-A*31:01 variant, more common in Japanese and
Europeans.
48
The HLA genes code for proteins that form an immunologic
complex found on all nucleated cells. This complex is responsible for
presenting both self and foreign peptides to immune cells, such as T
cells.49 When a foreign peptide is presented and then recognized by
a T cell, there is an immunologic response. Examples of peptides
that may be recognized as foreign include viruses, bacteria, tumor
antigens, and drugs. Although this complex may play a role in druginduced reactions seen with HLA variants, there is still significant
uncertainty as to whether or not there are other mechanisms at
play.50 Evidence has suggested that drug concentrations are also
higher in patients who experience cutaneous reactions, hinting that
CYP loss-of-function alleles and HLA variants may work
synergistically to increase a patient’s risk of SJS and TEN.50 This
possibility is supported by the fact that not all patients who carry an
HLA allele will experience a cutaneous reaction.
47
HLA class I genes are highly polymorphic.51 Variants within these
genes are thought to result in structural changes in the HLA complex
that increase the recognition and subsequent response of the
immune system to certain drugs, resulting in hypersensitivity.
Reactions related to these variants tend to be dermatologic in nature
with or without systemic involvement, ranging from a mild
maculopapular rash or progressing to more severe cases of SJS and
TEN.
CASE 4-6, QUESTION 2: What is the appropriate advice for the pharmacist to
provide to J.C. given her presentation?
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J.C. should be advised to seek care immediately at the closest
and most accessible hospital emergency department. SJS and TEN
have significant associated complications and typically require
inpatient treatment with fluids, corticosteroids, analgesics, nutritional
supplementation, and antibiotics. Mortality rates with TEN are
estimated to be >30%.48 In all cases, the suspected offending agent
should be discontinued with no rechallenge.
CASE 4-6, QUESTION 3: In questioning J.C., the pharmacist learns that she has
no prior history of adverse drug or food reactions. She is of Chinese descent
and has never had genetic testing. What would have been an appropriate
course of action for a patient with J.C.’s history before starting carbamazepine
therapy?
Differing from CYP enzyme genotypes, HLA phenotypes do not lie
on a spectrum, and patients are reported as positive if at least one
variant is present or negative if no variant is present. Carriers of
certain HLA variants are at increased risk for cutaneous ADRs;
however, recommendations and guidelines for preemptive testing
are either nonspecific or lacking. Other HLA variants have been
linked to liver injury, leading to the theory that the amount and
location of HLA expression may be a determining factor relating to
which organ systems are affected.51 Determining when and whom to
test before therapy is typically left to the discretion of the provider or
institution-specific protocols. The exception to this is for the HIV drug
abacavir, for which CPIC and the U.S. Food and Drug Administration
(FDA) recommendations state that all patients should have HLA-
B*57:01 testing before initiating regimens with either of these
therapies.
52
Variants of the HLA genes are seen more commonly within certain
ethnicities. In some cases, owing to the high prevalence of allele
carrier status in these populations, patients with particular ethnic
backgrounds may be recommended for testing. Certain Asian
populations are known to have higher rates of certain variants,
warranting caution when using certain therapies (Table 4-6). In the
case of carbamazepine and J.C., her physician may have justifiably
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ordered pharmacogenomic testing to determine her HLA-B*15:02
carrier status based on the fact that she identifies as Chinese.
Relying on self-reported ethnicity can be problematic, however,
because many people are not fully knowledgeable of their complete
lineage.
Table 4-6
HLA Variants, Affected Drugs, and Population Incidence
HLA
Variant
Drugs With Associated
Adverse Cutaneous
Reactions
Highest Variant Frequencies by
Ethnicity
48,54–57
HLA-
B*57:01
Abacavir Caucasian: 5%–8%
HLA-
B*58:01
Allopurinol Han Chinese: 6%–8%
Korean: 12%
HLA-
B*15:02
Phenytoin,
carbamazepine
Han Chinese: ~10%
Populations from Hong Kong, Thailand,
Malaysia, Vietnam, Philippines, India,
and Indonesia: >5%
HLA-
A*31:01
Carbamazepine Northern European: 2%–5%
Japanese: up to 17.5%
HLA, human leukocyte antigen.
Sources: Karnes JH, Rettie AE, Somogyi AA, et al. Clinical Pharmacogenetics
Implementation Consortium (CPIC) guideline for CYP2C9 and HLA-B genotypes
and phenytoin dosing: 2020 update. Clin Pharmacol Ther. 2021;109(2):302–309.
doi:10.1002/cpt.2008; Phillips EJ, Sukasem C, Whirl-Carrillo M, et al. Clinical
Pharmacogenetics Implementation Consortium guideline for HLA genotype and
use of carbamazepine and oxcarbazepine: 2017 update. Clin Pharmacol Ther.
2018;103(4):574–581. doi:10.1002/cpt.1004; Martin MA, Hoffman JM, Freimuth
RR, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for
HLA-B genotype and abacavir dosing: 2014 update. Clin Pharmacol Ther.
2014;95(5):499–500. doi:10.1038/clpt.2014.38; Saito Y, Stamp LK, Caudle KE, et
al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for
human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015
update. Clin Pharmacol Ther. 2016;99(1):36–37. doi:10.1002/cpt.161.
Testing recommendations vary, but if a patient is a known carrier
of an HLA variant, it is recommended that they avoid the use of
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drugs for which there is an HLA-variant–associated risk of adverse
reaction.
40,47,52,53
CYP2D6 PECULIARITIES
CASE 4-7
QUESTION 1: P.F. is a 37-year-old-female with a history of depression and
anxiety who presents to the local pharmacy with a printed report from a for-profit
pharmacogenomic testing company. The report states that P.F. is an extensive
metabolizer for CYP2D6, and she is concerned that her paroxetine is still not
providing any relief of her depressive symptoms despite having taken the drug
correctly for the past 3 months.
What information would you want to know about the testing modality the
company used before answering her question regarding the interpreted
genotype?
There are several pharmacogenomic testing platforms, with the
majority of commercially available panels being SNP based. The
advantages of SNP-based platforms include lower cost, faster
turnaround time, vendor-provided interpretation software, and
reliable calling for known variants. The main disadvantage of SNPbased platforms is that they are only capable of delivering results for
the genes and specific variants on the panel. If a person carries any
unique or rare variants, the SNP-based panel will not detect them.
This scenario increases the risk of there being a discrepancy
between a patient’s reported genotype and phenotype, or how they
actually process and/or respond to drugs affected by the variant.
CYP2D6 is also a very polymorphic gene, and it is not uncommon for
individuals to carry more than two allele copies. Differences in the
CYP2D6 copy number is referred to as copy number variation
(CNV), and knowing the CNV is extremely important in interpreting a
person’s CYP2D6 genotype.58 Once CNV is determined, all of the
allele copies identified should be genotyped, which is not always
possible on commercially available assays because the process
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requires extra primers. Another issue is that CYP2D7 is a
pseudogene (a gene with no function) that can accidentally be
included in the CYP2D6 analysis if the assay is not designed
correctly.
59
In addition to targeted SNP-based assays, pharmacogenetic data
can come from other types of genetic tests. The coding region of
DNA is the exome, and whole-exome sequencing or assays
targeting specific regions of interest within the exome can provide
significant pharmacogenomic data. With exome sequencing,
uncommon or previously unidentified variants could be reported,
often deemed variants of unknown significance (VUS) because their
clinical effects are not yet known. Because there remains a lot of
variability in how exomes are analyzed and reported, both sensitivity
and specificity of results are mutable. As a result, it can be a
challenge to manage and meaningfully interpret exome findings,
particularly when a distinct phenotype cannot be readily correlated.
In addition, exome- and whole-genome sequencing can yield
incidental or secondary findings of disease-state markers. The hybrid
test, a sequence-based targeted panel of pharmacogenes, has
become a hot area of development, attempting to incorporate the
best features of both sequencing and limited gene interrogation.
P.F.’s report shows a genotype of CYP2D6 *1/*2 but does not
indicate the copy number of the CYP2D6 gene. This is a red flag for
interpretation and should prompt the pharmacist to call the company
to obtain a detailed explanation of the assay used and understand
how P.F.’s extensive metabolizer phenotype was determined.
CASE 4-7, QUESTION 2: Per the company, P.F.’s copy number was equal to 3.
Does this information change the interpretation of P.F.’s phenotype?
A CYP2D6 copy number of 3 with *1/*2 alleles is associated with
the ultrarapid metabolizer phenotype.58 Unique to CYP2D6, an
activity score is calculated based on the number of copies of the
gene present because all influence drug metabolism. The activity
score was introduced by Gaedigk in 2013 to better categorize the
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metabolism status of persons with extra copies of the gene.60 An
example of how CNV can change a phenotype is represented in
Table 4-7.
Table 4-7
CYP2D6 Genotypes, Phenotypes and Activity Scores
58-60
Gaedigk A. Complexities of CYP2D6 gene analysis and interpretation. Int Rev
Psychiatry. 2013;25(5):534–553. doi:10.3109/09540261.2013.825581; Riffel AK,
Dehghani M, Hartshorne T, et al. CYP2D7 sequence variation interferes with
TaqMan CYP2D6 (*) 15 and (*) 35 genotyping. Front Pharmacol. 2015;6:312.
doi:10.3389/fphar.2015.00312; Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al.
Standardizing CYP2D6 genotype to phenotype translation: consensus
recommendations from the clinical pharmacogenetics implementation consortium
and Dutch Pharmacogenetics Working Group. Clin Transl Sci. 2020;13(1):116–
124. doi:10.1111/cts.12692.
As an ultrarapid metabolizer, P.F.’s lack of response to a standard
paroxetine dose aligns with her phenotype. Per the associated CPIC
guideline, her provider should choose another drug not primarily
metabolized via the CYP2D6 pathway.61 Because P.F. spent 3
months taking a medication with no response, this case serves as a
prime example of the important role pharmacogenomic data can play
in guiding treatment choices before initiating therapy.
CASE 4-8
QUESTION 1: You have started to work at a pediatric hospital and notice that
codeine is not orderable in the electronic medical record. When you ask a
coworker, he informs you that the black box warning placed on all codeine
products by the FDA in 2012 has resulted in the majority of pediatric institutions
removing the drug from formularies.
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What specific genotype is correlated with the risk of life-threatening apnea
with codeine use?
Codeine is metabolized by CYP2D6 to the active metabolite
morphine, which provides analgesic properties. CYP2D6 ultrarapid
metabolizers can generate morphine at higher rates, exceeding the
body’s ability to convert it to less toxic metabolites and resulting in
life-threatening apnea.62 Approximately 4% of the population are
thought to be CYP2D6 ultrarapid metabolizers.
63
In contrast, there are several loss-of-function variants across
ethnicities that confer little to no CYP2D6 enzyme function, resulting
in a lack of morphine formation. The loss-of-function *4 allele, for
example, is found in 6% of African Americans, 5% of Asians, and in
up to 18% of European Americans/Europeans.63 Patients carrying
loss-of-function CYP2D6 alleles are likely to show decreased
response to codeine.
64
IMPACT OF PEDIATRIC ENZYME
DEVELOPMENT ON PHARMACOGENOMICS
CASE 4-9
QUESTION 1: As part of a voluntary research study in the neonatal intensive
care unit (NICU), pharmacogenomic results are returned to the provider for an
ex-30 week, 36.5-week corrected gestational age female. The provider notes
that her genotype for CYP2C19 is *17/*17, which would typically indicate that
she is an ultrarapid metabolizer for this enzyme. The provider states he would
like to start her on voriconazole for a presumed fungal infection and asks what
the dosing should be given her genotype.
What other information would be necessary to recommend a voriconazole
dose for this infant?
Voriconazole is metabolized via multiple enzyme pathways
including CYP3A4, CYP2C9, and CYP2C19, with the most
significant contribution coming from CYP2C19.65 The Royal Dutch
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Pharmacists Association has guidelines in place recommending
monitoring of voriconazole serum concentrations for CYP2C19-poor
and CYP2C19-intermediate metabolizers because 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.
66
Given this patient’s young age, multiple complex factors need to
be considered for dosing, both genetic and nongenetic. Because
voriconazole is dosed by body weight, the actual body weight of the
child is necessary for an appropriate dose calculation. Drug–drug
interactions should also be considered if the patient is taking
medications that induce or inhibit enzymes in the drug’s pathway.
Other variables contributing to complicated infant dosing and
clearance unpredictability include developing GI and renal function
and fluctuations in body fat and water composition affecting density
of drug distribution.67 In addition, although the patient’s genotype
suggests 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.
67,68
CYP enzyme development occurs at variable rates over time,
making it difficult to determine the contribution of pharmacogenomic
variants on optimal dosing (Fig. 4-3).
69-71
An excellent summary
review of enzyme maturation by Kearns and colleagues was
published in the New England Journal of Medicine in 2003.
67
CYP1A2, for example, is virtually undetectable at birth, with initial
development of low-level enzyme concentrations being seen over
the first month of life. Although general trends are observed, it is also
understood that development rates vary among individuals
throughout childhood, particularly in the first year of life.67 Given this
consideration, pharmacogenomics in the neonatal and infant
population may be a less influential factor than it is in older children
and adults, and its overall contribution remains unpredictable
because few studies are dedicated to the effects of
pharmacogenomic variants in the youngest patients. Therefore, it is
particularly important to monitor drug concentrations, response, and
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toxicities in the younger pediatric population and to dose adjust
accordingly. Voriconazole is of particular concern with this group
because evidence suggests that current pediatric dosing
recommendations could lead to subtherapeutic concentrations and a
general increased risk of treatment failure.
72
Figure 4-3 CYP2C19 enzyme activity by age. (Adapted from Ward
RM, Kearns GL. Proton pump inhibitors in pediatrics: mechanism of
action, pharmacokinetics, pharmacogenetics, and
pharmacodynamics. Paediatr Drugs. 2013;15(2):119–131.
doi:10.1007/s40272-013-0012-x; Koukouritaki SB, Manro JR, Marsh
SA, et al. Developmental expression of human hepatic CYP2C9 and
CYP2C19. J Pharmacol Exp Ther. 2004;308(3):965–974.
doi:10.1124/jpet.103.060137.)
FAMILIAL IMPLICATIONS OF
PHARMACOGENETICS
CASE 4-10
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