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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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CI, confidence interval; IA, intermediate acetylator; OR, odds ratio; RA, rapid
acetylator; RR, risk ratio; SA, slow acetylator.
Sources: Pasipanodya JG, Srivastava S, Gumbo T. Meta-analysis of clinical
studies supports the pharmacokinetic variability hypothesis for acquired drug
resistance and failure of antituberculosis therapy. Clin Infect Dis. 2012;55(2):169–
177. doi:10.1093/cid/cis353; Sun F, Chen Y, Xiang Y, Zhan S. Drug-metabolising
enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver
injury: a meta-analysis. Int J Tuberc Lung Dis. 2008;12(9):994–1002; Wang PY,
Xie SY, Hao Q, Zhang C, Jiang BF. NAT2 polymorphisms and susceptibility to antituberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis.
2012;16(5):589–595. doi:10.5588/ijtld.11.0377; Ben Mahmoud L, Ghozzi H,
Kamoun A, et al. Polymorphism of the N-acetyltransferase 2 gene as a
susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian
patients with tuberculosis. Pathol Biol (Paris). 2012;60(5):324–330.
doi:10.1016/j.patbio.2011.07.001; Du H, Chen X, Fang Y, et al. Slow Nacetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced
hepatotoxicity: a meta-analysis. Mol Biol Rep. 2013;40(5):3591–3596.
doi:10.1007/s11033-012-2433-y; Huang YS, Chern HD, Su WJ, et al.
Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for
antituberculosis drug-induced hepatitis. Hepatol Baltim Md. 2002;35(4):883–889.
doi:10.1053/jhep.2002.32102.
Table 4-3
NAT2 Genotype–Based Dosing Recommendations for Isoniazid
Study
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2
Sun
et
al
‘
et
Wang
al
”
Ben
Mahmoud
2
Du
et
al
'
Huang
Pasipanodya
al
et
vs
vs
vs
vs
vs
In
RA
RA
in
RA
Result
no
Overall
subgroup
Asian
hepatotoxicity
risk
T
2.52
OR
T
risk
hepatotoxicity
_
Aslan
OR
_
non
OR
Asian
-
T
hepatotoxicity
risk
tion
regimen
T
risk
hepatotoxicity
;
4.3
Cl
OR
Overall
:
T
risk
hepatotoxicity
1
OR
3
Cl
(
Caucasian
risk
T
hepatotoxicity
2.8
Cl
OR
(
t
of
risk
treatment
RAs
(
Cl
2
RR
signlficant
1.5
Cl
(
(
4.9
:
:
1.5
-
2.5
:
-
no
significant
3
:
I
-
1.5
2.7
-
analysis
for
)
4.3
-
for
3.3
Cl
:
3.7
Cl
(
in
for
18
for
3
9
)
for
,
6
)
2
failure
)
finding
SAs
SAs
-
)
7.1
1.3
10.5
-
combina
SAs
SAs
finding
SAs
for
)
-
Type
Study
)
)
Chlnese
Japanese
Indian
East
Caucasian
Japan
China
Taiwan
India
Korea
Turkey
Switzerland
%
USA
8
)
(
Tunislan
Caucasian
Asian
Middle
Eastern
Brazilian
Taiwan
United
Kingdom
Asia
East
Africa
United
States
Prague
analysis
-
Meta
case
5
control
N
=
133
cases
492
Controls
analysis
Meta
-
14
N
case
=
11
474
1446
26
et
28
et
al
al
2
’
Observational
W
Meta
N
1198
2921
Observational
W
Meta
W
Asian
cases
Controls
=
65
analysis
-
26
=
cases
Controls
224
=
-
analysis
3471
=
3
.
studies
studies
-
hepatotoxicity
(
control
studies
-
non
Asian
-
hepatotoxicity
(
-
case
control
-
case
control
Metric
Prevalence
hepatotoxicity
control
SA
hepatotoxicity
hepatotoxicity
SA
IAs
and
Prevalence
hepatotoxicity
control
hepatotoxicity
SA
RA
treatment
vs
SA
of
of
SA
status
cases
risk
risk
SA
status
cases
risk
failure
risk
AE, adverse effects; DILI, drug-induced liver injury; NR, no result; NS,
nonsignificant; TF, treatment failure.
Source: Azuma J, Ohno M, Kubota R, et al. NAT2 genotype guided regimen
reduces isoniazid-induced liver injury and early treatment failure in the 6-month
four-drug standard treatment of tuberculosis: a randomized controlled trial for
pharmacogenetics-based therapy. Eur J Clin Pharmacol. 2013;69(5):1091–1101.
doi:10.1007/s00228-012-1429-9.
Several questions remain as to how to most safely and
appropriately incorporate NAT2 genotype results into a widespread
clinical application. For example, pediatric patients such as A.S. offer
a unique set of challenges because recommended isoniazid starting
doses are within a higher range (10–15 vs 5 mg/kg for adults), and
dose modifications based on genotype have not been studied in this
population. Genotype concordance with predicted phenotype has
also been found to be lower in pediatric patients.30 In addition, ethnic
variation among study results also suggests that testing may be
more beneficial in certain groups, namely, those with Asian ancestry.
As is the case when using ethnicity to determine whether to
complete any genetic test, self-reported ancestry is not always a
reliable means of predicting someone’s actual genetic lineage. With
a foundation of promising preliminary studies, a continued focus on
the NAT2 genotype effects on isoniazid safety has the potential to
result in institutions and organizations adopting policies to
proactively test NAT2 in the context of isoniazid treatment to both
prevent adverse drug events and increase treatment success.
PHARMACODYNAMIC IMPLICATIONS
2
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Dosing
kg
/
al
et
’
Recommendation
(
2.5
mg
-
)
7.5
(
mg
—
Standard
AE
)
kg
/
)
kg
/
Dl
TF
Dl
TF
Dl
TF
LI
LI
LI
77.8
22
4.7
26.8
4.2
39.5
%
%
2
%
%
%
%
kg
mg
5
Genotype
/
0
0
4.5
15
Based
-
%
%
%
%
Summary
Slow
Intermediate
Rapid
of
Results
Genotype
50
Standard
50
%
%
From
dose
dose
Azuma
Based
-
decrease
(
mg
5
increase
Dosing
P
003
.
NR
NR
NR
NS
013
CASE 4-2
QUESTION 1: E.F. is a 51-year-old male status post ST-elevation myocardial
infarction (STEMI) and atrial fibrillation with a residual left ventricular thrombus.
Despite aggressive dose escalations of warfarin, his international normalized
ratio (INR) will not budge above 1.7. His current dose of warfarin is 10 mg daily
and he reports no dietary changes or excessive vitamin K intake. There are no
drug–drug interactions identified in his regimen. The cardiology team asks
about pharmacogenomic testing.
What is known about the genes involved in warfarin response that would
impact E.F.’s INR?
Warfarin works by inhibiting vitamin K epoxide reductase complex
subunit 1 (VKORC1), a key enzymatic component in the vitamin K
clotting pathway.31 By inhibiting VKORC1, synthesis of vitamin K–
dependent clotting factors II, VII, IX, and X is reduced, and
anticoagulation is achieved under conditions where thrombosis is a
concern, such as atrial fibrillation. The amount of VKORC1 present
in a person is linked to the VKORC1 gene, a key pharmacodynamic
consideration. Patients with the GG genotype at VKORC1
rs9923231 are considered warfarin insensitive, meaning they are
likely to require larger doses of warfarin to effectively inhibit the
VKORC1 pathway. The AA genotype has been associated with
lesser amounts of VKORC1, and therefore these patients are
warfarin sensitive and require lower doses of warfarin for inhibition
and anticoagulation.
32
Another significant factor affecting warfarin dosing and response is
the effect of genetic variants on warfarin metabolism. Warfarin is
taken orally as a racemic mixture of R- and S-enantiomers, and its
subsequent metabolism is complex, involving multiple genes and
pathways. The primary pathway of the S-enantiomer, the more active
form of the drug, is via the CYP2C9 enzyme.32 CYP2C9 is the
predominant enzyme pathway responsible for >25% of the variation
in warfarin metabolism. CYP2C9 is highly polymorphic, with several
known variants within the population linked to reduced metabolic
rates, including the CYP2C9 *2 and *3 alleles. Reduced warfarin
metabolism leads to increased concentrations of the active form of
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the drug. These patients may require lower warfarin doses, and thus
may be at increased risk for bleeding using standard dosing
algorithms.
32
A more recent gene of focus with limited evidence relating to
warfarin sensitivity is CYP4F2.33 CYP4F2 affects the metabolism
and, therefore, the physiologic levels of vitamin K. Patients with the
TT genotype for CYP4F2 rs2108622 are thought to maintain higher
concentrations of vitamin K, and therefore require ~1 mg more
warfarin per day than do patients with the CC genotype. Although
current dosing models focus strictly on CYP2C9 and VKORC1
genotypes for warfarin initiation, CYP4F2 has shown early promise
as a potential factor for strengthening the effectiveness of dose
prediction algorithms in some ethnicities.
34
It is important to remember that many nongenetic factors such as
age, weight, diet, smoking status, medication interactions, and
others contribute to great variability in warfarin dosing within patient
populations. Drug–drug interactions in which the CYP2C9 enzyme
may be induced or inhibited can affect both the rate of warfarin
metabolism and the pharmacogenomic phenotype, a phenomenon
termed phenoconversion. In addition, a diet high in vitamin K will
make warfarin less effective because this facilitates increased
synthesis of vitamin K–dependent clotting factors. Algorithms for
determining appropriate starting doses for patients older than age 18
years based on both nongenetic and genetic factors are available at
www.warfarindosing.org. Close monitoring of INR is also
recommended to ensure proper anticoagulation and reduced risk of
bleeding.
CASE 4-2, QUESTION 2: What other drugs are significantly affected by the
CYP2C9 pathway?
CYP2C9 is estimated to play a role in the metabolism of up to 20%
of commonly used medications.35 From these medications, several
associations have been found linking variants in the CYP2C9
pathway to both increased rates of adverse drug events and variable
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medication response. Examples of such drugs include phenytoin,
certain nonsteroidal anti-inflammatory drugs (NSAIDs, such as
celecoxib and diclofenac), sulfonylureas, losartan, and certain statins
(such as fluvastatin and simvastatin). Patients with *2 or *3 alleles
may be at increased risk for toxicities at standard doses of drugs that
are processed through the CYP2C9 pathway because of decreased
metabolism and increased parent drug concentrations and may
require reduced dosing or increased monitoring.
IMPLICATIONS IN ACUTE TOXICITY
Many known variants within the genes that code for enzyme proteins
exist, possibly affecting the rate at which the enzyme is able to
metabolize drugs through its pathway. These variants may result in
either reduced enzyme function, leading to increased concentration
of the parent drug, or increased enzyme activity with decreased
concentrations of a parent drug. The clinical effects of variants
depend on whether the parent drug is pharmacologically active or a
prodrug.
CASE 4-3
QUESTION 1: T.B. is a 10-year-old male admitted for status epilepticus, treated
with intravenous (IV) lorazepam and IV fosphenytoin on presentation, aborting
the seizures. His past medical history is significant for congenital
hydrocephalus, a ventriculoperitoneal (VP) shunt, and refractory epilepsy
secondary to an in utero right middle cerebral artery (MCA) stroke. On day 5 of
his hospitalization, he is still extremely lethargic, and his free phenytoin level is
high, peaking at 3 μg/mL on day 2 and 1.4 μg/mL on day 5. Looking at his
records, he received the initial loading dose of IV fosphenytoin 500 mg
phenytoin sodium equivalents (PE) (18 mg PE/kg) followed by a single
maintenance dose of IV fosphenytoin 140 mg PE (5 mg PE/kg) 5 hours later on
day 1 of the hospitalization (Fig. 4-2). He has no clinically relevant drug–drug
interactions, and his albumin is normal.
What is a possible reason for the toxicity T.B. is experiencing?
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Figure 4-2 Free phenytoin levels (Case 4-3).
Phenytoin/fosphenytoin serum concentrations can be difficult to
control and are complicated by multiple factors including Michaelis–
Menten kinetics or capacity-limited metabolism. Drugs that follow
Michaelis–Menten kinetics go from first to zero order, meaning that
metabolism increases with increasing concentration until enzyme
saturation takes place.36 Once saturation is reached, drug plasma
concentrations can increase to toxic levels in a fast and
unpredictable manner. In addition, many factors affect an individual’s
safe and effective phenytoin dose, including albumin levels, other
medications in the patient’s regimen, and pharmacogenetics.
Phenytoin has many chronic effects associated with long-term use
including hepatotoxicity, osteoporosis, megaloblastic anemia,
gingival hyperplasia, hirsutism, and peripheral neuropathy.37 In the
acute setting of toxic plasma concentrations or an overdose,
phenytoin toxicity can manifest with a variety of signs and symptoms,
including central nervous system (CNS) effects (dizziness,
confusion, drowsiness, and ataxia) as well as gastrointestinal (GI)
upset and nausea. Phenytoin is also associated with severe
cutaneous reactions such as Stevens–Johnson syndrome (SJS) and
toxic epidermal necrosis (TEN), discussed in Case 4-6.
3.5
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2.5
Phenytoin
Free
3
Levels
0
Day
X
normal
Day2Day3Day4Day
1
low
5
Day
6
Generalized
Day
7
Day
8
i
-
E
CT
3.1
>
0.5
2
5
.
1
Generalized
0
Day
normal
Day
9
high
Day
10
Fosphenytoin is a prodrug that is converted by plasma esterases
to the active drug phenytoin. Phenytoin is further metabolized by
CYP2C9 to phenytoin arene oxide, which is then broken down to
multiple metabolites that are eventually excreted.
38,39
The
contribution of these various metabolites to toxicity and efficacy of
phenytoin is not well understood.
T.B. is found to carry a loss-of-function variant for CYP2C9 with
the genotype *1/*2. With loss of CYP2C9 enzyme function comes
decreased breakdown of the active drug phenytoin at standard
doses. Given the narrow therapeutic index of phenytoin and the
drug’s propensity to cause side effects, T.B. ultimately experienced
drug toxicity and accompanying symptoms. The evidence relating
genotypes such as T.B.’s to the development of adverse drug events
is strong, and CPIC has published dosing guidelines based on the
CYP2C9 genotype, summarized in Table 4-4.40 Note that only the
maintenance, not the loading dose, has adjustment
recommendations so that acute seizure activity can be immediately
terminated.
Table 4-4
CYP2C9 Genotype–Based Dosing Recommendations for
Phenytoin/Fosphenytoin
CYP2C9
Metabolizer
Status
Sample
Genotype(s) Recommendation
Extensive
metabolizer
*1/*1 Initiate therapy with recommended maintenance
dose.
Intermediate
metabolizer
*1/*2, *1/*3 Consider 25% reduction of recommended starting
maintenance dose and adjust according to
therapeutic drug monitoring and response.
Poor
metabolizer
*2/*2, *3/*3,
*2/*3
Consider 50% reduction of recommended starting
maintenance dose and adjust according to
therapeutic drug monitoring and response.
CASE 4-4
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QUESTION 1: J.P. is a 110.23-pound (50-kg), 17-year-old female status post
kidney transplant. She is currently receiving azathioprine 100 mg by mouth (PO)
daily to prevent rejection. She is brought to the emergency department 5 days
after starting the medication with lethargy, fever, and malaise. A white blood cell
(WBC) count comes back with a critically low value of 0.9 × 109 cells/L (normal
range, 4.5–11.0 × 109 cells/L), with an absolute neutrophil count (ANC) of 760
cells/μL (normal range, 2500–6000).
What factors might explain such severe neutropenia, and what
pharmacogenomic test should be ordered for J.P.?
Azathioprine is an immunosuppressive agent in the thiopurine
class, acting as a prodrug of 6-mercaptopurine. These drugs are
purine analogs and antagonize purine synthesis, inhibiting synthesis
of DNA, RNA, and proteins.41 Thiopurines are used in a variety of
conditions including renal transplant, rheumatoid arthritis, certain
cancers, and inflammatory bowel disease.
Azathioprine is further metabolized to 6-mercaptopurine (an active
drug) via glutathione S-transferase (GST) reduction. 6Mercaptopurine is then converted into the active 6methylmercaptourine ribonucleotide (6-MMPR) and several inactive
metabolites such as 6-methylmercaptopurine (6-MMP) through
multiple pathways.42 The two primary enzymes contributing to 6mercaptopurine breakdown are TPMT and hypoxanthine guanine
phosphoribosyltransferase (HPRT). TPMT metabolism results in the
generation of the inactive metabolite 6-MMP, whereas HPRT
contributes to a pathway that leads to the generation of active 6MMPR and 6-thioguanine nucleotide (6-TGN) metabolites.
43
Furthermore, active 6-TGN metabolites are then inactivated by
TPMT. The accumulation of active 6-TGN metabolites via HPRT is
associated with myelosuppression with thiopurine therapy. In
summary, TPMT acts as the detoxifying enzyme for drugs in the
thiopurine class, and its activity is directly linked to risk of drug
toxicities.
The severe neutropenia J.P. experienced 5 days after beginning
azathioprine is very likely the result of starting a full dose (2
mg/kg/day) in the setting of a homozygous variant TPMT genotype,
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such as *3B/*3C. Owing to the near-absent enzyme level produced
by homozygous variants, the TGN metabolites build up, resulting in
severe, and sometimes, life-threatening neutropenia.
It is important to note that the genotype *3B/*3C is nearly
impossible to distinguish from the less clinically impactful
heterozygous genotype of *1/*3A on most commercially available
TPMT assays. In cases of suspected homozygous variant status,
parental studies may be necessary for absolute determination.
Alternative therapy or a 90% reduction in the azathioprine dose is
advised for J.P.’s TPMT genotype. In the case of a heterozygous
genotype such as *1/*3C, the dose would be decreased by 30% to
70%.
44
DRUG TARGET IMPLICATIONS
CASE 4-5
QUESTION 1: L.K. is a 45-year-old female referred for interpretation of
pharmacogenomic results provided by a certified clinical lab as part of a
research study. The report states that her genotype for SLCO1B1 is CC. L.K.
asks if she is at risk for severe muscle pain, or myopathy, with statin therapy
that she heard about on a recent TV malpractice commercial.
What information do you need to answer her question?
“Statins” or β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA)
reductase inhibitor drugs are associated with muscle toxicity ranging
from mild aches to the development of severe debilitating myopathy
and rhabdomyolosis in a segment of the population.45 Regardless of
severity, this adverse drug event is a common cause for drug
discontinuation.46 Recent published literature links the risk of
developing these muscle-related side effects to certain variants in
the SLCO1B1 gene.
Keeping in mind that a raw result from DNA analysis is essentially
a string of As, Cs, Ts, and Gs within each individual gene, the CC
genotype for SLCO1B1 information provided by L.K. is insufficient.
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To accurately review the available evidence and make
recommendations, it is essential to know the actual variant location
that the CC call was based on. Although there are multiple
polymorphisms that have been identified in the SLCO1B1 gene, only
a few are linked to clinical effect.
46
An rs number, or rsID, is used to point to a specific nucleotide
location within a gene. Known SNPs within a gene are defined by
rsID for the purpose of clinical guidelines and research reporting.
This ensures standardization and proper assessment of variants. For
SLCO1B1, the rsID most commonly associated with development of
myopathy with HMG-CoA reductase inhibitors is rs4149056.46 This
rsID should be provided with results to make the proper
assessments, and most clinical labs will include the associated rsID
numbers for any SNP results to help clinicians make appropriate
decisions about drug selection and dose alteration.
CASE 4-5, QUESTION 2: The clinical lab confirms the SLCO1B1 genotype CC
call was based on rs4149056. What is your answer to L.K.’s question regarding
her risk of developing severe myopathy with statin use?
The C allele at SLCO1B1 rs4149056 has been associated with
decreased statin intracellular transport and clearance.46 SLCO1B1 is
a transporter protein with a primary function of drug uptake into the
liver. Variants affecting the hepatic uptake of drugs via SLCO1B1
ultimately increase overall area under the curve (AUC) and drug
exposure, resulting in higher risks of adverse drug events such as
myopathy. Patients with a homozygous variant status such as L.K.
are at significantly increased risk for developing muscle toxicity with
statin use. Although all statins may have adverse event profiles
linked to this variant, the evidence is strongest for simvastatin.
Published CPIC guidelines for simvastatin with SLCO1B1 rs4149056
variant status are summarized in Table 4-5.
Table 4-5
SLCO1B1 Genotype–Based Dosing Recommendations for HMG-
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