Clinical UM Guideline

This document addresses genotype testing for individual polymorphisms which can identify variants of specific genes associated with abnormal and normal drug metabolism. Such testing is used to identify individuals with certain gene variants which may potentially be able to receive higher or lower doses of some drugs, or should avoid some drugs altogether, to improve the likelihood of achieving clinical goals as well as lessening the risk of adverse drug effects.

Testing for NS3 Q80K for individuals being treated for Hepatitis C virus is NOT addressed in this document.

Note: For additional information regarding pharmacogenomics, please see:

• CG-GENE-10 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability and Congenital Anomalies
• CG-GENE-13 Genetic Testing for Inherited Diseases
• GENE.00010 Panel and other Multi-Gene Testing for Polymorphisms to Determine Drug-Metabolizer Status

Medically Necessary:

Genotype testing for genetic polymorphisms of Human Leukocyte Antigen B*1502 (HLA-B*1502) to determine the drug-metabolizer status of individuals for whom the use of carbamazepine is being proposed is considered medically necessary when both of the criteria below have been met:

1. The individual is from a population who is at high risk due to ethnic heritage; and
2. There are no other alternatives to the use of carbamazepine.

Genotype testing for identification of the CYP2C19 variant of Cytochrome P450 is considered medically necessary to determine the drug-metabolizer status of individuals who meet either of the following criteria:

1. The individual is currently undergoing treatment with clopidogrel and has not been tested: or
2. The use of clopidogrel is being proposed.

Genotype testing for Human Leukocyte Antigen B (HLA-B*5701) is considered medically necessary before beginning treatment with abacavir for persons infected with HIV-1.

Genotype testing for identification of the CYP2D6 variant of Cytochrome P450 to determine the drug-metabolizer status of individuals being considered for treatment with eliglustat is considered medically necessary.

Genotype testing for identification of the CYP2D6 variant of Cytochrome P450 to determine the drug-metabolizer status of individuals with Huntington’s disease being considered for treatment with a dosage of tetrabenazine greater than 50 mg per day is considered medically necessary.

Genotype testing to determine the presence of the HLA-B*58:01 allele in individuals from a population who are at high risk due to ethnic heritage for whom the use of allopurinol is being considered for treatment is considered medically necessary.

Genotype testing to determine the presence of CYP2C9 genotype before administration of siponimod is considered medically necessary.

Genotype testing for individual genetic polymorphisms to determine thiopurine methyltransferase (TPMT) genotype is considered medically necessary prior to the initiation of thiopurine medication when the results of phenotype testing is indeterminate.

Not Medically Necessary:

Genotype testing for individual genetic polymorphisms for individuals who potentially may receive the drugs listed above is considered not medically necessary when the criteria or circumstances detailed above are not met.

Genotype testing for individual genetic polymorphisms to determine drug-metabolizer status is considered not medically necessary in all other circumstances.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

CYP2C19
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure code listed above when criteria are not met.

HLA-B
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for the following

CYP2D6
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

CYP2C9
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

TPMT
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure code listed above when criteria are not met.

Other polymorphism genes
When services are Not Medically Necessary:

Identification of genetic factors that influence drug absorption, metabolism, and action at the receptor level has the potential to allow for individualized therapy based on optimal drug effectiveness and a minimized toxicity profile. Drug efficacy and toxicity vary substantially between individuals. Because drugs and doses are typically adjusted to meet individual requirements as needed by using trial and error, clinical consequences may include a prolonged time to optimal therapy and serious adverse events. It has been found that inherited deoxyribonucleic acid (DNA) sequence variation (polymorphisms) in genes for drug-metabolizing enzymes may have a significant effect on the efficacy or toxicity of a drug. This field of research is referred to as pharmacogenomics.

It has been proposed that genotype testing for certain genes to detect polymorphisms will allow physicians to predict side effects to drugs and to tailor a drug regimen based on an individual’s genetic make-up. It may be that genotype testing will improve the choice of drug, or the dose of the drug, when the drug in question has a narrow therapeutic dose range, when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in individuals with certain polymorphisms.

The role of genotype testing for individual polymorphisms to identify variants of specific genes associated with abnormal metabolism, has been evaluated for a number of drugs.

Carbamazepine (Tegretol^®)

There has been study into the role of HLA-B*1502 mutations in the occurrence of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome in ethnic Han Chinese individuals receiving treatment with the anticonvulsant drug carbamazepine (CBZ). A molecular study by Hung et al. (2006) identified this genetic variation as a contributor to this reaction. Based on data reviewed by an expert panel, the United States Food and Drug Administration (FDA) decided to place a black-box warning on the label of carbamazepine as follows:

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported during treatment with Tegretol. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher. Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. HLA-B*1502 is found almost exclusively in patients with ancestry across broad areas of Asia. Patients with ancestry in genetically at risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment with Tegretol. Patients testing positive for the allele should not be treated with Tegretol unless the benefit clearly outweighs the risk.

Chen and colleagues (2001) conducted a study of 4877 carbamazepine-naïve subjects who were genotyped for the HLA-B*1502 allele. B*1502 allele-positive subjects were given an alternative medication while negative subjects were treated with carbamazepine. The authors then compared the incidence of SJS and TEN in the study population to historical controls. Results demonstrated that a mild, transient rash developed in 4.3% of B*1502 positive subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS/TEN did not develop in any of the HLA-B*1502–negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS/TEN (0.23%) would translate into approximately 10 cases among study subjects (p<0.001).

Other genetic mutations have also been studied as having clinical impact on the outcomes of individuals who may undergo treatment with carbamazepine. McCormack and others (2011) described a study looking at the association of the HLA-A*3101 allele and the incidence of carbamazepine-related complications. This study included 65 subjects who had experienced carbamazepine-related complications and 3987 control subjects. An independent genome-wide association study demonstrated a significant association between subjects with the HLA-A*3101 allele and the incidence of carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. Further study is warranted to understand the impact of genetic testing on the rate of occurrence of complications in subjects carrying the HLA-A*3101 allele. He and colleagues (2014) studied the impact of several genes on the development of SJS in a population of 225 ethnic Han Chinese subjects (n=25 with SJS, 200 non-SJS controls) who had been exposed to carbamazepine. They observed statistically significant differences in EPHX1 c.337T>C polymorphisms between SJS group subjects and controls in terms of allelic and genotypic frequencies (p=0.011 and p=0.007, respectively). They stated that the C allele and the C-G diplotype of EPHX1 may play important roles in increasing the risk of CBZ-SJS/TEN development (odds ratio [OR], 0.478; p=0.011; OR, 0.21; p=0.025, respectively). No significant associations were reported between ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA or BAG6 genes and carbamazepine dose, or dose-adjusted concentration in carbamazepine-tolerant subjects.

In a 2018 systematic review and meta-analysis by Chouchi and colleagues, the authors evaluated the strength of the associations between reported single-nucleotide polymorphisms in potential genes and adverse drug reactions in participants with epilepsy on carbamazepine therapy. The analysis was limited to participants with epilepsy not using any other types of treatment that might induce adverse drug reactions. A total of nine studies were included for meta-analysis. These studies evaluated the associations between the HLA-B*15:02 polymorphism and serious cutaneous reactions (SCRs) including carbamazepine-induced SJS and carbamazepine-induced SJS/TEN in Asian populations with epilepsy. The authors noted that HLA-B*15:02 polymorphisms were significantly associated with carbamazepine SCR risk (OR: 27.325, 95% confidence interval [CI], 9.933-51.166). In Han Chinese participants, the allele was significantly associated with carbamazepine SCRs (OR: 42.059; 95% CI, 9.587-184.514). The HLAB* 15:02 polymorphism was strongly associated with carbamazepine-induced SJS (OR: 152.089; 95% CI, 34.737-665.901). In the Asian population, the HLA-B*15:02 polymorphism was significantly associated with carbamazepine-induced SJS/TEN (OR: 13.993; 95% CI, 7.291-26.856) and in particular, in the Han Chinese population (OR: 17.886; 95% CI, 8.411-38.034). Limitations include a small group of included studies and small sample sizes which led to publication bias and lack of other ethnicities studied. Even with the small number of included studies, the results show that the HLA-B*15:02 polymorphism can induce SCRs among the Asian population using carbamazepine.

Clopidogrel (Plavix^®)

Focus has been placed on the impact of drug metabolizer status testing for individuals prescribed clopidogrel. Several published nonrandomized, controlled studies addressed the use of testing for genetic variants in CYP4502C19, ABCB1, CYP2A5, and P2RY12 (Collet, 2009; Mega, 2009; Simon, 2009). These studies found that mutations in these genes, especially CYP2C19 variants, have significant effects on cardiovascular health outcomes. Mega and colleagues (2009) conducted a study addressing the impact of CYP-450 gene variants on clinical response to clopidogrel treatment. This study included 162 healthy subjects and 1477 subjects with acute coronary disease being treated with clopidogrel. Carriers of at least one CYP2C19 allele had a 32.4% reduction in the active metabolite of clopidogrel, a 9% decrease in maximal platelet aggregation response, a 300% increase in the risk of stent thrombosis (ST), and relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with non-carriers.

A study by Simon and others (2009) enrolled 2208 subjects with acute myocardial infarction (MI) who were receiving clopidogrel therapy. The authors reported a significantly increased risk of adverse cardiovascular events in individuals with CYP2C19 variants when compared to those with no mutations (21.5% vs. 13.3%). Among the 1535 participants who also underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among individuals with two CYP2C19 loss-of-function (LOF) alleles was 3.58 times the rate among those with none.

The current FDA label for clopidogrel (FDA, 2022) has a black-box warning that addresses the use of pharmacogenetic testing. The warning states:

• Effectiveness of Plavix depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
• Tests are available to identify patients who are CYP2C19 poor metabolizers.
• Consider use of another platelet P2Y₁₂ inhibitor in patients identified as CYP2C19 poor metabolizers.

Mega and colleagues published the findings of a large meta-analysis conducted in 2010. This report included 9685 subjects who were treated with clopidogrel in nine studies. The findings indicated that subjects with one or two LOF CYP2C19 alleles had a significantly increased risk of composite endpoint events (hazard ratio [HR], 1.55; p=0.01; HR, 1.76; p=0.002, respectively). Additionally, these subjects had an increased risk of stent thrombosis when compared to non-carriers of LOF alleles.

A study by Simon and colleagues (2011) involved 2210 subjects being treated for acute MI who were genotyped for CYP2C19 polymorphisms. They reported that the presence of two CYP2C19 LOF alleles was significantly associated with the risk of in-hospital death and major myocardial events at 1 year for individuals with acute MI (adjusted odds ratio 6.67) and those undergoing percutaneous coronary interventions (PCI) (adjusted odds ratio 6.87). They also studied the association of PON1 polymorphism with major myocardial events, but reported that no statistically significant association was found.

Mega and others (2011) conducted a randomized double-blind trial that enrolled 333 subjects with cardiovascular disease who were genotyped for CYP2C19*2 LOF allele status. Non-carriers of the allele received either 75 mg or 150 mg daily dose of clopidogrel in one of two blinded 28-day long blocks. Carriers of the CYP2C19*2 allele received 75 mg, 150 mg, 225 mg, or 300 mg doses of clopidogrel in a blinded sequence of four 14-day long blocks. For the 75 mg dosage, both CYP2C19*2 hetero- and homozygotes had significantly higher on-treatment platelet reactivity than non-carriers (p<0.001 for both groups). Higher doses of clopidogrel in CYP2C19*2 heterozygotes significantly reduced the proportion of non-responders to 10% in both 225 mg (8 of 75 subjects, p<0.001) and 300 mg (7 of 73 subjects, p<0.001). In CYP2C19*2 homozygotes, higher doses of clopidogrel did not provide similar benefits, with 80% of this group being non-responders at 75 mg and 60% still being non-responders at the 300 mg dosage. The authors reported that in CYP2C19*2 heterozygotes, a dose of 225 mg provided similar platelet reactivity scores to that found with non-carriers receiving a 75 mg dose. In CYP2C19*2 homozygotes, not even the 300 mg dose provided equivalent platelet reactivity to non-carriers. There were no deaths, cerebrovascular events, or Thrombolysis in Myocardial Infarction (TIMI) major or minor events reported in either group at any dose level. This study provides significant evidence to demonstrate that CYP2C19*2 guided dosing of clopidogrel can provide significant benefits in platelet reactivity measures. Further data would be helpful in determining if this also results in significant health outcomes in terms of decreased cardiovascular disease-related deaths and complications.

Sibbing and colleagues (2009) published the results of a case series study of 2485 subjects undergoing coronary stent placement after pre-treatment with 600 mg of clopidogrel. Genotyping of all subjects was conducted and the results found that 805 subjects (73%) were CYP2C19 wild-type homozygotes and 680 subjects (27%) carried at least one *2 allele. The authors reported that cumulative 30-day incidence of stent thrombosis was significantly higher in CYP2C19*2 allele carriers vs. wild-type homozygotes (HR=3.81; p=0.007). The risk of stent thrombosis was highest (2.1%) in subjects with the CYP2C19 *2/*2 genotype (p=0.002). The authors concluded that CYP2C19*2 carrier status is significantly associated with an increased risk of ST following coronary stent placement.

This group published another study in 2010 (Sibbing, 2010) involving 1524 subjects undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotyping for CYP2C19*17 allelic variant and adenosine diphosphate (ADP)-induced platelet aggregation were assessed. For both heterozygous (n=546) and homozygous (n=76) *17 allele carriers, significantly lower ADP-induced platelet aggregation values were found vs. wild-type homozygotes (n=902; p=0.039 and p=0.008, respectively). Furthermore, CYP2C19*17 allele carriage was found to be significantly associated with an increased risk of bleeding, with the highest risk observed for CYP2C19*17 homozygous subjects (p=0.01). A multivariate analysis confirmed the independent association of CYP2C19*17 allele carriage with platelet aggregation values (p<0.001) and the occurrence of bleeding (p=0.006). However, no significant influence of CYP2C19*17 was detected in relation to the incidence of stent thrombosis (p=0.79). The authors concluded that CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.

The results of two large placebo-controlled, randomized controlled trials (RCTs) were published by Pare et al. (2010). The two studies included a total of 5059 subjects randomized to receive either clopidogrel or placebo and followed for the occurrence of primary and secondary composite outcomes. The authors concluded that “no significant difference in the effect of clopidogrel treatment on clinical outcomes was observed when subjects were stratified according to metabolizer status.” However, some increase in efficacy was seen in subjects with gain-of-function alleles in terms of reduced ischemic events.

A 2019 randomized, open-label trial by Claassens and colleagues reported on individuals who underwent percutaneous coronary intervention to assess whether CYP2C19 genotype-guided strategy for selection of oral P2Y₁₂ inhibitors can reduce the risk of bleeding without increasing thrombotic risk. Participants were randomized in a 1:1 fashion to either the genotype-guided group (n=1242) or the standard treatment with either ticagrelor or prasugrel (n=1246). Participants without a CYP2C19 loss-of function allele received clopidogrel while carriers of a loss-of-function CYP2C19 allele received ticagrelor or prasugrel. There were two primary outcomes including adverse clinical events and major or minor bleeding. Follow-up was 12 months. In the genotype-guided group, combined primary outcomes occurred in 63 participants (5.1%) and in 73 participants (5.9%) in the standard-treatment group. There were 122 participants (9.8%) that had primary bleeding in the genotype-guided group and 156 participants (12.5%) in the standard-treatment group. The authors concluded “a CYP2C19 genotype–guided strategy for selection of oral P2Y₁₂ inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding.”

In 2011, three meta-analyses were published looking at the health-related outcomes of CYP2C19 genotype testing for individuals receiving clopidogrel. One of these reported that CYP2C19*2 carrier status was significantly associated with increased risk of cardiovascular events. The other two found no such benefit.

The first study, by Jin and colleagues, included a total of eight prospective cohort studies including 2345 subjects carrying the CYP2C19*2 LOF allele and 5935 wild-type controls. The authors reported that the summary odds ratio demonstrated a statistically significant association in increased cardiac mortality (p=0.007), myocardial infarction (p=0.002), and stent thrombosis (p=0.0001). However, while these findings point to a major role of the CYP2C19 allele in the incidence of major cardiovascular events, the study itself was comparatively small and did not include any RCT data.

In the second study, Bauer et al. looked at the data collected in 15 studies encompassing 28,368 subjects. They found the random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 LOF allele vs. non-carriers was 1.77 (p<0.001). However, the authors note that this finding is subject to significant small study bias and replication diversity. When adjusted for these factors, the significance of this finding was nullified. Furthermore, the odds ratio for major cardiovascular events and stent thrombosis was likewise non-significant. The overall quality of the epidemiological evidence reviewed was graded as low, and the authors’ conclusion was that “… at the current state of accumulated information, there is not sufficiently robust and consistent evidence that CYP2C19 represents a strong susceptibility gene modifying the clinical efficacy of clopidogrel.”

The third meta-analysis was published by Holmes and others and included 32 studies encompassing 42,016 subjects. Six of the included studies were RCTs. As with the Bauer study previously discussed, this study concluded that “this systematic review and meta-analysis does not demonstrate a clinically important association of genotype with cardiovascular outcomes with the possible exception of stent thrombosis.” The report stated that when statistically significant analyses were re-run with only studies that included greater than 200 subjects, the original statistically significant findings were nullified. The authors concluded that significant small study bias existed in the body of evidence. This is supported by positive results of the Harbord test for small study bias (p=0.001). The authors also state that selective outcome reporting and genotype misclassification errors impair the available evidence.

Mao (2013) reported a meta-analysis of 21 studies involving 23,035 subjects. They reported that compared with non-carriers of the CYP2C19 variant allele, carriers were found to have an increased risk of adverse clinical events (OR=1.50; p=0.0003), myocardial infarction (OR=1.62; p<0.00001), stent thrombosis (OR=2.08; p<0.00001), ischemic stroke (OR=2.14; p=0.001) and repeat revascularization (OR=1.35; p=0.004), but not of mortality (p=0.500) and bleeding events (p=0.930). They concluded that the presence of the CYP2C19 polymorphism is significantly associated with risk of adverse clinical events in clopidogrel-treated subjects.

In 2014, Sorich and others reported the results of a meta-analysis of 24 studies with ≥ 500 participants involving 30,076 subjects, looking at the effects of the CYP2C19 genotype on clopidogrel effectiveness. Data was stratified by the predominant clopidogrel indication (percutaneous coronary intervention [PCI] versus non-PCI) and ethnic population (white versus Asian) of each primary study. The association between carriage of more than one CYP2C19 LOF allele and major cardiovascular outcomes differed significantly (p<0.001) between studies of whites not undergoing PCI (relative risk [RR], 0.99; n=7043), whites undergoing PCI (RR, 1.20; n=19,016), and Asians undergoing PCI (RR, 1.91; n=10,017). Similar differences were identified in secondary analyses of two CYP2C19 LOF alleles, stent thrombosis outcomes, and studies with ≥ 200 participants. The conclusions stated that the reported association between CYP2C19 LOF allele carriage and major cardiovascular outcomes differs based on the ethnic population of the study and, to a lesser extent, the clopidogrel indication. This is potentially of major importance given that over 50% of Asians carry at least one CYP2C19 LOF allele.

In 2015, Osnabrugge published a systematic review and critical assessment of 11 overlapping meta-analyses that involved 30 primary studies that addressed the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel. Of the 11 meta-analyses, 8 reported statistically significant associations, with mean effect size ranging from 1.26 to 1.96. Of those 8 studies, 5 reported associations between the presence of loss-of-function polymorphisms and clinical endpoints, and the other 3 reported no statistically significant pooled effect or could not pool data to a high degree of heterogeneity. The 4 studies concluding no association were the most recently published. All 11 studies reported a statistically significant association with CYP2C19 LOF alleles and stent thrombosis with mean effect size 1.77 to 3.85. The authors reported that all included meta-analyses reported significant heterogeneity, which was handled in significantly different manners. Publication bias was assessed in 9 of the 11 meta-analyses included; 6 concluded that some publication bias was present and 2 did not find evidence of bias. The remaining study provided a funnel plot, but no discussion of the data. The authors concluded that meta-analyses on the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel differed widely with regard to assessment and interpretation of heterogeneity and publication bias.

Doll and colleagues (2016) reported the results of a study involving 2236 subjects receiving clopidogrel or prasugrel, looking at the association of CYP2C19 metabolizer status (extensive vs. reduced) and their primary endpoints of cardiovascular death, MI, or stroke. They reported finding no association between CYP2C19 metabolizer status and the primary endpoints (HR=0.86). Subjects in either group had similar rates of the primary endpoint whether treated with prasugrel (HR=0.82) or clopidogrel (HR=0.91; p=0.495). After adjusting for clinical and treatment variables, they stated that extensive metabolizers had a lower risk of MI vs. reduced metabolizers (HR=0.80), but the risk of other outcomes were similar. Reduced metabolizers had significantly higher mean P2Y12 reaction units versus extensive metabolizers when treated with clopidogrel (39.93), but not with prasugrel (3.87).

In 2017, Cui and colleagues published a meta-analysis involving 5769 subjects in 15 studies with an aim to evaluate a relation between T744C, G52T, and C34T polymorphisms in the P2Y12 receptor gene in relation to clopidogrel resistance in subjects with cardiovascular disease. The authors reported that a G52T and C34T polymorphism might be associated with clopidogrel resistance as evident from platelet function assay (p<0.05), and that there was no significant association found between T744C polymorphism and clopidogrel resistance in various genetic models (p>0.05). This study did not demonstrate a link between the testing for these polymorphisms and improved clinical outcomes when treatment is guided by their results.

A systematic review and meta-analysis was performed by Pan and colleagues (2017) and included 15 studies involving of 4762 subjects with stroke or transient ischemic attack (TIA) treated with clopidogrel. It was concluded that, in subjects with ischemic stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles are at a greater risk of stroke and composite vascular events than non-carriers (p<0.001). The authors also found there was no significant difference in bleeding rates between CYP2C19 carriers and non-carriers (p=0.59), and other genetic variants were not associated with clinical outcomes associated with clopidogrel efficacy for acute ischemic stroke or TIA. While these findings may suggest the need for genetic testing when clopidogrel is used as the treatment option for stroke or TIA, the meta-analysis lacked statistical heterogeneity among the included studies, one study accounted for 31% of the subjects in the meta-analysis, and the authors disclosed publication bias for the primary end point.

The results of these large, well-done meta-analyses call into question earlier assessments regarding the efficacy of CYP2C19 genotyping for individuals receiving clopidogrel. Additional data from large-scale, well-done prospective RCTs is needed to further clarify this issue.

Abacavir (Ziagen^®)

The role of genetic polymorphisms in the metabolism and tolerance of various drugs used to treat HIV-1 infection has been of major interest. The most widely studied of these interactions is between the histocompatibility complex allele for HLA-B*5701 and the occurrence of abacavir (ABC) hypersensitivity reactions (ABC-HSR). Since shortly after the FDA approval of ABC in 1999, studies began to arise associating the presence HLA-B*5701 with the occurrence of ABC-HSR. A large study addressing the incidence of ABC-HSR was conducted by Hetherington and colleagues (2001). Using data from approximately 200,000 subjects enrolled in various ABC clinical trials, the authors conducted a retrospective review of pooled adverse events. Of the 31,096 subjects identified as having hypersensitivity reactions, 1302 (4.3%) were identified as having ABC-HSR. Of these, 176 (9.8%) were considered definitive ABC-HSR cases after failing rechallenge with ABC. These findings were supported by a later study by the same authors that found the incidence of ABC-HSR to be approximately 4% in a case control study of 197 subjects from the Glaxo-SmithKlein database (Hetherington, 2002). Mallal and others (2002) were the first to publish the results of a trial demonstrating a positive correlation between ABC-HSR and the presence of HLA-B*5701. This small study of 200 HIV-1 subjects exposed to ABC identified 18 individuals with definitive ABC-HSR (9%). However, the Mallal study went further and typed all subjects for HLA loci. They reported that HLA-B*5701 occurred in only 4% of ABC tolerant subjects and 78% in subjects with ABC-HSR (p<0.0001), strongly supporting their hypothesis that the presence of the HLA-B*5701 haplotype was strongly associated with ABC-HSR. They went on to calculate that the presence of HLA-B*5701 had a positive predictive value for ABC-HSR of 100% and a negative predictive value of 97%. These findings were supported by a retrospective study by Rauch and colleagues (2008) that performed genotyping on 131 individuals with suspected ABC-HSR. While these authors did not conduct confirmatory rechallenge to confirm ABC-HSR, they did conduct a blind case review of subjects’ medical records, sorting them into likely ABC-HSR (n=27, 21%), unlikely ABC-HSR (n=43, 33%), and uncertain ABC-HSR (n=61, 47%). They found that HLA-B*5701 was present in 31% of likely cases compared to 1% of unlikely cases (p<0.0001). A retrospective case control study looked at the sensitivity and specificity of HLA-B*5701 genotyping in subjects receiving ABC enrolled 130 white and 69 black subjects for suspected ABC-HSR (Saag, 2008). Positive skin-patch testing identified 42 (33.2%) white and 5 (7.2%) black subjects with confirmed ABC-HSR. All confirmed ABC-HSR subjects were HLA-B*5701 positive (sensitivity=100%), regardless of race. Among all subjects with clinically suspected ABC-HSR, sensitivity was 44% for white subjects and 14% for black subjects. Specificity for white control subjects was 96% and 99% for black subjects. In the most rigorous study to report on this issue, Mallal and colleagues conducted a prospective randomized, double-blind study involving 1956 subjects with HIV-1 who were ABC naïve (2008). Subjects were randomized to undergo prospective HLA-B*5701 screening, with positive subjects forgoing ABC treatment. The control group received routine care with ABC without HLA-B*5701 screening. Similar to the previous studies, the prevalence of HLA-B*5701 was 5.6%. The authors reported that immunologically confirmed ABC-HSR occurred in 2.7% of subjects in the screening group vs. none in the control group. The calculated negative predictive value reported to be 100% and positive predictive value was 47.9%. The existing data, discussed above, adequately demonstrate that the HLA-B*5701 genotype is strongly associated with ABC-HSR, and that screening for this genotype significantly decreases the occurrence of ABC-HSR in individuals who have been prescribed ABC.

A 2020 study by Quiros-Roldan and colleagues evaluated the relationship between HLA-B*5701 and ABC-HSR. Their focus was on the prevalence of hypersensitivity reaction in non-carriers of the HLA-B*5701 allele. In this retrospective review, there were 3144 HIV-positive individuals with known HLA-B*5701 pattern. A total of 171 individuals were known carriers of HLA-B*5701 and 2973 were non-carriers of HLA-B*5701. In the HLA-B*5701 carrier group, 32 participants were treated with a first abacavir-containing regimen while 1769 in the HLA-B*5701 non-carrier group 1769 participants were treated with a first abacavir-containing regimen. The abacavir-containing regimen was discontinued for toxicity/intolerance in 22 participants who were known carriers of HLA-B*5701 and all were found to have a certain ABC-HCR. There were 169 participants in the non-carrier group who discontinued the abacavir-containing regimen due to toxicity/intolerance. Certain ABC-HSR was found in 85 participants while 84 participants were found to have adverse events, but not HSR.

In 2019, the Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV recommend the following:

• The Panel recommends screening for HLA-B*5701 before starting patients on an abacavir (ABC)-containing regimen to reduce the risk of hypersensitivity reaction (HSR).
• HLA-B*5701-positive patients should not be prescribed ABC.
• The positive status should be recorded as an ABC allergy in the patient’s medical record.
• When HLA-B*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and monitoring for any signs of HSR.

Eliglustat (Cerdelga^®)

In 2014, the FDA approved eliglustat “for the long-term treatment of adult subjects with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.”

The evidence addressing the use of CYP2D6 genotyping for individuals who may be prescribed eliglustat for the treatment of Gaucher disease was presented in the FDA’s Clinical Pharmacology and Biopharmaceuticals Review of Eliglustat from June 24, 2014. This document describes data addressing CYP2D6 testing for individuals prescribed eliglustat from several sources. The first is a series of three unpublished Phase I and II safety and effectiveness studies involving 151 subjects. All subjects were genotyped and followed for drug response and subject pools were stratified into poor metabolizers (PM), intermediate metabolizers (IM), and ultra-rapid metabolizers (URM). The data demonstrates that there is significant variation in eliglustat metabolism based on CYP2D6 status. Another source of data presented in the FDA Review document is data derived from computer simulations of metabolic response derived from computer modeling using the SimCYP^® software package. Again, this data demonstrated that there was significant metabolic response to eliglustat dependent upon CYP2D6 status.

Additionally, two peer-reviewed published articles have addressed the use of CYP2D6 genotyping in populations given eliglustat. The first, by Lukina (2010), was an open-label case series study involving 26 subjects with Gaucher disease. In the results section, the authors briefly comment that, “Lower exposure was associated with lower administered dose, greater body weight, and higher CYP2D6 metabolic activity.”  No further data or comments are provided, including any outcomes data related to CYP2D6 genotype. The other study was a small Phase I dose-finding RCT involving healthy volunteers evaluating the safety, tolerability, and pharmacokinetics in escalating doses of eliglustat in 36 subjects. The authors commented in the discussion section, “As expected, because Genz-99067 is predominantly metabolized by CYP2D6, participants with genotypes corresponding to slower CYP2D6 metabolism exhibited higher exposure.”

Tetrabenazine (Xenazine^®)

There is very little available data addressing the possible benefits of such genotype testing for individuals who may receive treatment with tetrabenazine. The only available peer-reviewed published study to report the issue was published by Mehanna and colleagues in 2013. This study involved 127 subjects with Huntington disease (chorea) who were genotyped for CYP2D6. Of this population, 100 were identified as EMs, 14 were IMs, 11 as PMs, and 2 as URMs. The authors noted that the URM subjects required a significantly longer titration period compared to other metabolizer groups (8 vs 3.3, 4.4, and 3 weeks, respectively; p<0.01) to achieve optimal benefit. This group also required a higher average daily dose than the other subjects, but this difference did not reach statistical significance. The treatment response was less robust in the IM group when compared with the EM subjects (p=0.013), but there were no statistically significant differences between the various groups with regard to adverse effects. They concluded that, aside from the need for a longer titration in the URMs, there are no distinguishing features of individuals with various CYP2D6 genotypes, and, “therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered.”

However, the FDA-approved label for tetrabenazine (FDA, 2019) states the following:

Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer (PM) or an extensive metabolizer (EM).

Despite the low level of evidence supporting the use of genotyping for individuals who may receive tetrabenazine, at this time the use of such testing for individuals who may receive a dose greater than 50 mg/day is supported by the practicing community based on a preponderance of caution.

Allopurinol (Zyloprim^®)

Allopurinol reduces serum and urinary uric acid concentrations. It is used as an antihyperuricemic agent for primary or secondary gout, for individuals with leukemia, lymphoma and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels, and for individuals with recurrent calcium oxalate calculi. Allopurinol has been known to cause a variety of cutaneous adverse drug reactions ranging from a mild form to drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Severe cutaneous adverse reactions constitute a set of life-threatening conditions which include drug rash with eosinophilia and systemic symptoms. The HLA-B*58:01 allele has been identified as a strong genetic marker for allopurinol-induced cutaneous adverse drug reactions in individuals of Asian descent.

In a 2015 study by Ko and colleagues, the authors used genotype testing to screen 2910 Taiwanese participants who had an indication for allopurinol for the HLA-B*58:01 allele. A total of 571 participants tested positive for the HLA-B*58:01 allele and were referred for an alternate drug treatment or counselled about severe cutaneous adverse drug reactions. There were 2339 participants who tested negative for the HLA-B*58:01 allele and were given allopurinol. Of those who tested negative, 155 participants did not take allopurinol and 11 participants were lost during follow-up. The remaining 2173 participants were monitored during treatment for 2 months with a weekly telephone interview. A mild and transient rash and itching occurred in 97 participants who received allopurinol. Three of the participants who had previously tested positive for HLA-B*58:01 showed symptoms of rash and itching after taking an alternative medicine (benzbromarone), not allopurinol. None of the participants who were receiving allopurinol and screened negative for HLA-B*58:01 developed severe cutaneous adverse drug reactions.

A 2016 meta-analysis by Wu and colleagues, reported on 21 pharmacogenetic studies, including 551 participants with allopurinol-induced cutaneous adverse drug reactions. There were 2370 allopurinol-tolerant controls from 16 matched studies. Most of the studies were conducted among East Asian populations. When considering only the severe form of cutaneous adverse drug reactions, the odds ratio of allopurinol-induced severe cutaneous adverse drug reactions for carrier of the HLA-B*58:01 allele was 92.06 (95% CI, 59.54-142.32, p<10-5) compared to 108.39 (95% CI, 73.73-159.36, p<10-5) for matched and population-based studies. Overall, the HLA-B*58:01 allele showed an odds ratio of 82.77 (95% CI, 41.63-164.58, p<10-5) with the risk of allopurinol-induced cutaneous adverse drug reactions compared to 100.87 (95% CI, 63.91-159.21, p<10-5) in population-based studies.

In a 2020 study by Low and colleagues, the authors reported on the association between HLA-B*58:01 and the risk of allopurinol-induced severe cutaneous reactions across different populations. There were 55 individuals with allopurinol-induced severe cutaneous reactions and 42 allopurinol-tolerant controls. The HLA-B*58:01 allele was found in 89.1% of participants with allopurinol-induced severe cutaneous reactions and 14.3% of participants in the allopurinol-tolerant control group. Analysis by ethnicity showed the Chinese population with HLA-B*58:01 allele had an increased risk of developing allopurinol-induced severe cutaneous reactions (OR,137.5, p< 0.0001) followed by the Malaysian population (OR,35.2, p< 0.0001). The Indian population included in the study was too small for meaningful analysis.

The 2020 American College of Rheumatology guideline for the management of gout conditionally recommends testing for the HLA-B*58:01 allele prior to the initiation of allopurinol in select populations including Southeast Asian descent and African Americans.

Siponimod (Mayzent^®)

In March 2019, the FDA approved siponimod for the treatment of relapsing forms of multiple sclerosis in adults. This approval was based on a double-blind, randomised, phase 3 study (Kappos, 2018). The CYP2C9 genotype has an impact on the metabolism of siponimod. As part of the FDA approval, CYP2C9 genotype determination should be assessed prior to administration. Dosing regimen is dependent on genotype CYP2C9, specifically *1/*3 or *2/*3 genotype. The current label (FDA, 2023) states the drug is “contraindicated in patients with a CYP2C9*3/*3 genotype.”

A 2019 pharmacokinentics study by Gardin and colleagues found approximately two to fourfold greater mean area under the curve siponimod plasma concentrations in subjects with CYP2C9*2/*3 and CYP2C9*3/*3 (poor metabolizers) versus CYP2C9*1/*1 genotype (extensive metabolizers), confirming the relevance of CYP2C9 activity on siponimod metabolism.

Thiopurine methyltransferase (TPMT)

The presence of mutations in the TPMT gene or variations in TPMT enzyme activity have the potential for development of toxicity in certain drugs, particularly thiopurine drugs, including azathioprine (AZA) and 6-mercaptopurine (6-MP). Assessment of TPMT enzyme activity has been proposed prior to initiation of thiopurine drugs to prevent treatment-related myelotoxicity. TPMT enzyme activity can be assessed by phenotype (the measurement of enzyme activity directly in circulating red cells), or by genotype (the genetic analysis for polymorphisms in leucocyte DNA), which can be used to predict activity. About 10% of the general population has genetic polymorphisms of the TPMT gene that can result in functional inactivation or markedly decreased activity of the enzyme and an increased risk of treatment-related leukopenia associated with thiopurine drugs.

The 2018 FDA label for azathioprine (Imuran^®) states that those with a TPMT deficiency may be at increased risk of myelotoxicity for conventional doses. Those with a known TPMT deficiency should be considered for alternative therapies. The 2020 FDA label for mercaptopurine (Purinethol^®) also suggests testing for TPMT for those with severe myelosuppression or repeated episodes of myelosuppression.

In a 2018 guideline on the management of Crohn’s disease in adults, the American College of Gastroenterology recommends that TPMT testing “should be considered before initial use of azathioprine or 6-mercaptopurine to treat patients with Crohn’s disease.” The recommendation cites Winter 2007 which notes: “Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease.”

A 2017 American Gastroenterological Association guideline on therapeutic drug monitoring in inflammatory bowel disease gives a conditional recommendation for routine TPMT testing (enzyme activity or genotype) for adults with inflammatory bowel disease being started on thiopurine drug therapy.

Because the TPMT gene is highly polymorphic, genotypic testing may misclassify some individuals. For this reason, assessment of TPMT enzyme activity (phenotyping) is generally preferable to genotype testing when testing is indicated (that is: prior to initiation of thiopurine drugs). In some cases, the results of phenotype testing for TPMT activity may be indeterminate; for example, following a blood transfusion, activity measured in blood may be reflective of the donor and not the individual.

Other Tests

Testing for genetic polymorphisms has also been proposed for a wide array of other drugs, involving many different conditions and enzymes. Testing for deficient dihydropyrimidine dehydrogenase (DPYD) activity (which could result in toxicities) has been explored in individuals initiating fluoropyrimidine therapy; however, at this time, the FDA does not require pharmacogenetic testing before fluoropyrimidine administration, and testing is not considered in accordance with generally accepted standards of medical practice. The 2023 National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guidelines in Oncology for colon cancer does not recommend routine DPYD testing prior to fluoropyrimidine therapy.

At this time, the available literature addressing such testing does not support use in accordance with generally accepted standards of clinical practice. Outcomes that require further attention include major adverse events, utilization of health resources, and time to clinically significant changes in condition using appropriate and validated measures.

Summary

While the potential of pharmacogenomics is intriguing for many clinical applications, it is imperative to establish evidence-based guidelines for healthcare professionals delineating the most effective courses of action based on such genotype testing results. Critical elements of assessing the effectiveness of such genetic tests include: (1) analytic (diagnostic) validity; (2) clinical validity; and (3) clinical utility. Analytic validity measures the technical performance of the test, in terms of accurately identifying the genetic markers to be measured. Clinical validity measures the strength of association between genetic test results and clinical parameters such as dose, therapeutic efficacy, or adverse events. Clinical utility, the ultimate goal of genetic testing, measures the ability of the test to improve clinical outcomes, such as whether prescribing or dosing based on information from genetic testing improves therapeutic efficacy or adverse event rate as compared with treatment without genetic testing.

Therefore, when considering whether or not a test to determine drug metabolizer status is appropriate in the treatment of individuals prescribed certain medications, specific issues need to be evaluated, including:

• A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with drug metabolism status; AND
• A biochemical or other non-genetic test is identified but the results are indeterminate, or the genetic status cannot be identified through such biochemical or other non-genetic testing; AND
• The results of the genetic test could impact the medical management of the individual with a resulting improvement in health outcomes.

The FDA has added language to the labels of many approved drugs to include pharmacogenomic information; however, evidence supporting pharmacogenomic biomarker testing varies widely. Wang and colleagues (2014) published a study evaluating evidence supporting pharmacogenomic biomarker testing in FDA drug labels. The study found that only a minority of labels cited evidence of clinical utility.

The FDA has also published a table of pharmacogenetic associations intended primarily for prescribers to help make prescribing decisions based on their judgment about which treatments are appropriate for individual persons. The FDA notes: “When a health care provider is considering prescribing a drug, knowledge of a patient's genotype may be used to aid in determining a therapeutic strategy, determining an appropriate dosage, or assessing the likelihood of benefit or toxicity.”

Also stating:

For the pharmacogenetic associations listed in this table, the FDA has evaluated and believes there is sufficient scientific evidence to suggest that subgroups of patients with certain genetic variants, or genetic variant-inferred phenotypes (such as affected subgroup in the table below), are likely to have altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events. […] the table does not necessarily mean the FDA advocates using a pharmacogenetic test before prescribing the corresponding medication, unless the test is a companion diagnostic. […] most of the associations listed have not been evaluated in terms of the impact of genetic testing on clinical outcomes, such as improved therapeutic effectiveness or increased risk of specific adverse events (FDA, 2022).

While current evidence regarding the use of genotyping tests for the determination of drug metabolizer status indicates that available testing methods may accurately identify genetic variations in an individual, in many cases such testing is not considered in accordance with generally accepted standards of medical practice. To support clinical utility, data should demonstrate that such testing, and the clinical decisions made based on the testing, result in a significant impact on health outcomes (including enhanced clinical effectiveness or in decreased short-term or long-term serious adverse events as compared to no testing).

Cytochrome P450: Refers to a family of 60 different enzymes involved in drug and toxin metabolism.

Genotype testing: Determining the DNA sequence in genes.

Metabolize: Refers to breaking down a drug so that it is no longer clinically active.

Polymorphisms: Refers to genetic variation between individuals resulting in differences in gene expression, in this case differing activity of various enzymes.

Peer Reviewed Publications:

1. Appell ML, Berg J, Duley J, et al. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics. 2013; 23(4):242-248.
2. Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 2011; 343:d4588.
3. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011; 364(12):1126-1133.
4. Chouchi M, Kaabachi W, Tizaoui K, et al. The HLA-B*15:02 polymorphism and Tegretol®-induced serious cutaneous reactions in epilepsy: An updated systematic review and meta-analysis. Rev Neurol (Paris). 2018; 174(5):278-291.
5. Claassens DMF, Vos GJA, Bergmeijer TO, et al. A genotype-guided strategy for oral P2Y₁₂ inhibitors in primary PCI. N Engl J Med. 2019; 381(17):1621-1631.
6. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009; 373(9660):309-317.
7. Cui G, Zhang S, Zou J, et al. P2Y12 receptor gene polymorphism and the risk of resistance to clopidogrel: a meta-analysis and review of the literature. Adv Clin Exp Med. 2017; 26(2):343-349.
8. Doll JA, Neely ML, Roe MT, et al. TRILOGY ACS Investigators. Impact of CYP2C19 metabolizer status on patients with ACS treated with prasugrel versus clopidogrel. J Am Coll Cardiol. 2016; 67(8):936-947.
9. Gardin A, Ufer M, Legangneux E, et al. Effect of fluconazole coadministration and CYP2C9 genetic polymorphism on siponimod pharmacokinetics in healthy subjects. Clin Pharmacokinet. 2019; 58(3):349-361.
10. He XJ, Jian LY, He XL, et al. Association of ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms with the risk of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy. Epilepsia. 2014; 55(8):1301-1306.
11. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359(9312):1121-1122.
12. Hetherington S, McGuirk S, Powell G, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther. 2001; 23(10):1603-1614.
13. Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011; 206 (24):2704-2714.
14. Hou Q, Li S, Li L, et al. Association between SLCO1B1 gene T521C polymorphism and statin-related myopathy risk: a meta-analysis of case-control studies. Medicine (Baltimore). 2015; 94(37):e1268.
15. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006; 16(4):297-306.
16. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005; 5(1):6-13.
17. Ismail R, Teh LK. The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients. J Clin Pharm Ther. 2006; 31(1):99-109.
18. Jin B, Ni HC, Shen W, et al. Cytochrome P450 2C19 polymorphism is associated with poor clinical outcomes in coronary artery disease patients treated with clopidogrel. Mol Biol Rep. 2011; 38(3):1697-1702.
19. Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018; 391(10127):1263-1273.
20. Ke CH, Chung WH, Tain YL, et al. Utility of human leukocyte antigen-B*58: 01 genotyping and patient outcomes. Pharmacogenet Genomics. 2019; 29(1):1-8.
21. Ko TM, Tsai CY, Chen SY, et al. Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. BMJ. 2015; 351:h4848.
22. Lenz O, Vijgen L, Berke JM, et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol. 2013; 58(3):445-451.
23. Low DE, Nurul-Aain AF, Tan WC, et al. HLA-B*58: 01 association in allopurinol-induced severe cutaneous adverse reactions: the implication of ethnicity and clinical phenotypes in multiethnic Malaysia. Pharmacogenet Genomics. 2020; 30(7):153-160.
24. Lukina E, Watman N, Arreguin EA, et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010; 116(6):893-899.
25. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359(9308):727-732.
26. Mallal S, Phillips E, Carosi G, et al.; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008; 358(6):568-579.
27. Mao L, Jian C, Changzhi L, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects. Arch Cardiovasc Dis. 2013; 106(10):517-527.
28. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011; 364(12):1134-1143.
29. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360(4):354-362.
30. Mega JL, Hochholzer W, Frelinger AL 3rd, et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA. 2011; 306(20):2221-2228.
31. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010; 304(16):1821-1830.
32. Mehanna R, Hunter C, Davidson A, et al. Analysis of CYP2D6 genotype and response to tetrabenazine. Mov Disord. 2013; 28(2):210-215.
33. Palanisamy N, Danielsson A, Kokkula C, et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res. 2013; 99(1):12-17.
34. Pan Y, Chen W, Xu Y, et al. Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Circulation. 2017; 135(1):21-33.
35. Paré G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010; 363(18):1704-1714.
36. Peterschmitt MJ, Burke A, Blankstein L, et al. Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers. J Clin Pharmacol. 2011; 51(5):695-705.
37. Quiros-Roldan E, Gardini G, Properzi M, et al. Abacavir adverse reactions related with HLA-B*57: 01 haplotype in a large cohort of patients infected with HIV. Pharmacogenet Genomics. 2020; 30(8):167-174.
38. Rauch A, Nolan D, Thurnheer C, et al.; Swiss HIV Cohort Study. Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study. Antivir Ther. 2008; 13(8):1019-1028.
39. Rojas L, Neumann I, Herrero MJ, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015; 15(1):38-48.
40. Saag M, Balu R, Phillips E, et al.; Study of hypersensitivity to abacavir and pharmacogenetic evaluation study team. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008; 46(7):1111-1118.
41. Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther. 2006; 31(5):493-502.
42. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010; 121(4):512-518.
43. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. 2009; 30(8):916-922.
44. Simon T, Steg PG, Becquemont L, et al. Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction. Clin Pharmacol Ther. 2011; 90(4):561-567.
45. Simon T, Verstuyft C, Mary-Krause M, et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360(4):363-375.  
46. Sorich MJ, Rowland A, McKinnon RA, Wiese MD. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet. 2014; 7(6):895-902.
47. Swaisland HC, Cantarini MV, Fuhr R, Holt A. Exploring the relationship between expression of cytochrome P450 enzymes and gefitinib pharmacokinetics. Clin Pharmacokinet. 2006; 45(6):633-644.
48. Tran A, Jullien V, Alexandre J, et al. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther. 2006; 79(6):570-580.
49. Veal GJ, Cole M, Chinnaswamy G, et al. Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma. Eur J Cancer. 2016; 55:56-64.
50. Wang B, Canestaro WJ, Choudhry NK. Clinical evidence supporting pharmacogenomic biomarker testing provided in US Food and Drug Administration drug labels. JAMA Intern Med. 2014; 174(12):1938-1944.
51. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005; 352 (21):2211-2221.
52. Winter JW, Gaffney D, Shapiro D, et al. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2007; 25(9):1069-1077.
53. Wu R, Cheng YJ, Zhu LL, et al. Impact of HLA-B*58:01 allele and allopurinol-induced cutaneous adverse drug reactions: evidence from 21 pharmacogenetic studies. Oncotarget. 2016; 7(49):81870-81879.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Agency for Healthcare Research and Quality. Technology Assessment: Reviews of selected pharmacogenetic tests for non-cancer and cancer conditions. November 12, 2008. Available at: http://www.cms.gov/medicare-coverage-database/details/technology-assessments-details.aspx?TAId=61&bc=BAAgAAAAAAAA&. Accessed on July 12, 2023.
2. American College of Gastroenterology. ACG clinical guideline: management of Crohn's disease in adults. 2018. Available at: https://journals.lww.com/ajg/Fulltext/2018/04000/ACG_Clinical_Guideline__Management_of_Crohn_s.10.aspx. Accessed on July 12, 2023.
3. American Gastroenterological Association. Guideline on therapeutic drug monitoring in inflammatory bowel disease. 2017. Available at: https://www.gastrojournal.org/action/showPdf?pii=S0016-5085%2817%2935963-2. Accessed on July 12, 2023.
4. American College of Rheumatology. Guidelines for the management of gout. 2020. Available at: https://www.rheumatology.org/Portals/0/Files/Gout-Guideline-Final-2020.pdf. Accessed on June 6, 2022.
5. Cerdelga^® [Product Information], Waterford, Ireland. Genzyme Corporation. August 2018. Available at : http://www.cerdelga.com/pdf/cerdelga_prescribing_information.pdf. Accessed on July 12, 2023.
6. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. December 2019. Available at: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf. Accessed on July 12, 2023.
7. Imuran^® [Product Information], Roswell, GA. Sebela Pharmaceuticals Inc. December 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf. Accessed on July 12, 2023.
8. Mayzent^® [Product Information], East Hanover, NJ. Novartis Pharmaceuticals Corp. January 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209884s015lbl.pdf. Accessed on July 12, 2023.
9. NCCN Clinical Practice Guidelines in Oncology®. © 2023 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on July 18, 2023.
   • Colon Cancer (V.2.2023). Revised April 25, 2023.
10. Plavix^® [Prescribing Information], Bridgewater, NJ. Sanofi Aventis. September 2022. Available at:  https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020839s074lbl.pdf. Accessed on July 12, 2023.
11. Purinethol^® [Prescribing Information], Irvine, CA. Stason Pharmaceuticals. December 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/009053s040lbl.pdf. Accessed on July 12, 2023.
12. Tegretol^® [Product Information], East Hanover, NJ. Novartis Pharmaceuticals Corp. March 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016608s115_018281_s058_018927s055_020234_s047.pdf. Accessed on July 12, 2023.
13. U.S. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceuticals Review. June 25, 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205494Orig1s000ClinPharmR.pdf. Accessed on July 12, 2023.
14. U.S. Food and Drug Administration (FDA). Table of Pharmacogenetic Associations. October 26, 2022. Available at: https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. Accessed on July 12, 2023.
15. Xenazine^® [Product Information], Washington, DC. Prestwick Pharmaceuticals. November 2019. Available at: http://www.lundbeck.com/upload/us/files/pdf/Products/Xenazine_PI_US_EN.pdf. Accessed on July 12, 2023.
16. Ziagen^® [Product Information], Research Triangle Park, NC. GlaxoSmithKlein. November 2020. Available at : https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020977s035,020978s038lbl.pdf. Accessed on July 12, 2023.
17. Zyloprim^® [Product Information], East Brunswick, NJ. Casper Pharma LLC. August 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016084s044lbl.pdf. Accessed on July 12, 2023.

Abacavir
Allopurinol
AmpliChip^™ Cytochrome P450 (CYP450) Genotype Test
Carbatrol^®
Cytochrome P450 (CYP450)
Cytochrome P450 2C9 (CYP2C9)
Equetro^®
Fluoroplex^®
Mayzent
Plavix^®
Polymorphisms, Drug Testing
Thiopurine methyltransferase (TPMT)
Ziagen

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