Pharmacogenetic Testing: When Is It Useful and Why Might ... · What is pharmacogenetics? •The term pharmacogenetics commonly refers to the study of how variations in a single gene

1

Pharmacogenetic Testing: When Is

It Useful and Why Might Our

Patients Ask Us to Do It?

December 8, 2018

Amy Pasternak, PharmD, BCPS

Clinical Assistant Professor

Clinical Pharmacist

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Objective

By the end of this session, participants will be able to

describe the current evidence for pharmacogenetic testing

and list available resources to stay up to date with

pharmacogenetic evidence.

Outline

• Introduction to pharmacogenetics

• Review pharmacogenetic resources

• Discuss pharmacogenetic testing strategies

• Describe challenges for translation of pharmacogenetics

• Provide examples of pharmacogenetics in clinical practice

• Describe interpretations of direct to consumer (DTC) tests

What is pharmacogenetics?

• The term pharmacogenetics commonly refers to the study of how variations in a single

gene affect drug response

• The term pharmacogenomics commonly refers to the study of how variations in many

genes (genome wide variations) affect drug response

• The terms pharmacogenetics and pharmacogenomics are often used interchangeably

• Genetic variations can affect drug response through multiple pathways including:

• Drug metabolizing enzymes

• Drug receptors

• Drug transporters

• Drug targets

Types of genetic variation

Germline

• Inherited genetic variants

• Thiopurine methyltranferase

(TPMT)

– Variants in gene found in ~10% of the

population

– Reduced enzyme activity Decreased

drug metabolism thiopurine drug

toxicity

Somatic

• Variants identified in cancer cells

• KRAS

– Mutated in approximately 40% of

colorectal cancer

– Confers resistances to the EGFR

inhibitors cetuximab and panitumumab

Pharmacogenetic terminology

Interpretation of pharmacogenetics can differ from other

types of genetics

1. Unique terminology – star allele nomenclature

Pharmacogenetic interpretation

2. In most cases, need to consider the composite phenotype

from both alleles

*Alleles Diplotype/

GenotypePhenotypeSNPrsID Recommendation

CYP2C19*1

Normal function

CYP2C19*2

No function

Intermediate

metabolizerCYP2C19 *1/*2

681 G

681 A

Standard dose

voriconazole

Avoid clopidogrel

Rs12769205

GA

Pharmacogenetic test results may report any or all of this information in the genotype report

Pharmacogenetic Resources

Clinical Pharmacogenetics

Implementation Consortium

• All resources freely available at cpicpgx.org

• Multidisciplinary, international consortium of

pharmacogenetic experts

• Develop evidence based guidelines on

HOW to apply pharmacogenetic results into

patient care

• DO NOT provide recommendations on

when to obtain testing


• CYP2C19

– Clopidogrel

– Citalopram

– Escitalopram

– Sertraline

– Voriconazole

– Tertiary amine TCAs

• CYP2C9

– Warfarin

– Phenytoin

• CYP2D6

– Codeine

– Paroxetine

– Noritriptyline

– Fluovoxamine

– Ondansetron

– Tamoxifen

• CYP3A5

– Tacrolimus

• DPYD

– 5-FU

– Capecitabine

• G6PD

– Rasburicase

• HLA-A

– Carbamazepine

• HLA-B

– Abacavir

– Allopurinol

– Carbamazepine

– Oxcarbazepine

• IFNL3

– Peginterferon

• SLCO1B1

– Simvastatin

• TPMT

– Azathioprine

– Mercaptopurine

– Thioguanine

• UGT1A1

– Atazanavir


FDA Pharmacogenomic

Biomarkers Table

• Includes all medications with

genetic information included

in package insert

• Few germline

pharmacogenes require

pharmacogenetic testing


Pharmacogenomics KnowledgeBase

• Available at pharmgkb.org

• Uses clinical annotations to rate the quality of

evidence for a drug-gene pair

Genotyping strategies

• Preemptive genotyping

– Patient has genotyping results prior to ever needing a

medication

• Reactive genotyping

– Genotyping is ordered because patient will received a

medication with a known interaction

Selecting a testing strategy

• Single gene tests

– Useful when you know what you are looking for

– Potentially greater chance of reimbursement

Example:

– Patient with HIV needs to initiate antiretroviral therapy and the

clinician would like to prescribe abcavir as a part of the regimen

– Single gene test for HLA-B*57:01 must be ordered prior to

prescription

Selecting a testing strategy

• Panel testing

– Variations in multiple genes are evaluated at the same time;

genes may or may not be related to the same drugs

– Potentially a good option when patients will receive multiple

kinds of therapies (oncology), have diverse therapeutic options

(psychology), or have many comorbid conditions

How do I find a test?

Genetic Testing Registry (GTR; https://www.ncbi.nlm.nih.gov/gtr/)

How do I pick a test?

Considerations when picking a test:

• Cost/insurance coverage

• Scope of medication interest

– Level of evidence for tested genes

– Disease implications of tested genes

• Report format and interpretation

• Patient ethnicity

Common challenges for translation:

Lack of term standardization

• Not all labs interpret genotypes into the same phenotypes

• Not all labs use the same terminology

Caudle et. al. Genetics in Medicine. 2017. Adapted supplementary Table 2.

*Terms in red represent terms that are discordant with CPIC terminology, and in some cases may change therapeutic recommendation

between labs for the same drug

Gene Genesight® Genecept® CNSDose® Neuropharmagen® Level of

evidence*

CES1 X 3

CYP1A2 X X X 3

CYP2B6 X X X 3

CYP2C19 X X X X 1

CYP2C9 X X X 1

CYP2D6 X X X X 1

CYP3A4 X X X 3

UGT1A1 X 3

UGT1A4 X 3

UGT2B15 X X 2


Level of evidence for drug-gene pairs

Bousman et al. Pharmacogenomics J. 2018.18;613-22; PharmGKB.org

*Highest level of evidence according to PharmGKB for any psychotropic medication (antidepressant, anxiolytic, anticonvulsant,

antipsychotic)


Interpretation of results

Many medication recommendations are “binned” into categories

Often limited explanations for:

• Why a medication is included in each “bin”

• Whether that means you shouldn’t use the medication or a

medication adjustment is recommended

Good Caution Avoid

• Often returned as a PDF documents

– Scanning into medical record can be hard to find

• Possible solutions

– Add to patient problem list

– Add to patient lab results


Storage of test results

Hoffman et al. Am J Med Genet C Semin Med Genet. 2014

Hicks et al. Pharmacotherapy. 2016


Patient expectations

E. Vessell, 1980s

If there’s so many challenges why would

we ever use pharmacogenetic testing?

Increase patient safety

Enhance clinical

services

Decrease adverse events

Increase patient

compliance

Decrease healthcare

costs

Improve patient risk stratification

Improve dosing

algorithms

Alessandrini et al. OMICS. 2016

Pharmacogenetics in practice

JK is a 34 YOM who presents to the ID clinic to discuss

switching to an alternative antiretroviral regimen for his HIV

infection. His physician wants to initiate therapy with

Triumeq® (dolutegrevir, abacavir, and lamivudine) once daily.

Pharmacogenetic consideration:

Abacavir has an FDA black box warning that requires

pharmacogenetic testing for HLA-B*57:01 prior to prescribing

Pharmacogenetics in Practice

JK had a pharmacogenetic test for HLA-B*57:01 five years ago

when he was initially diagnosed with HIV.

Implementation of Best Practice Advisories (BPA)

• Recommend testing if missing

• Prevent abacavir prescription if patient

positive for HLA-B*57:01

• Prevent duplicate HLA-B*57:01 tests

Medication Order

Drug: Triumeq (dolutegrevir, abacavir, lamivudine)

Dose: 1 capsule

Route: Oral

Frequency: Once daily

Warning: “This patient is positive for HLA-B*57:01 which

confers an increased risk for potentially life-threatening

hypersensitivity to abacavir. Selection of an alternative

antiretroviral is recommended.”

HLA-B*57:01 genotype: Positive for HLA-B*57:01



Enhance clinical

services


Increase patient

compliance

Decrease healthcare

costs


Improve dosing

algorithms


AP is a 24 YOF with a history of major depressive disorder.

She has been treated with multiple lines of therapy but has

either not tolerated or not responded to treatment.

Previously trialed antidepressant therapies:

• Paroxetine

• Citalopram

• Vorioxetine

• Sertraline


AP obtains a psychotropic pharmacogenetic panel test:

Desvenlafaxine

Levomilnacipran

Vilazodone

Trazadone

Sertraline

Citalopram

Escitalopram

Fluoxetine

Venlafaxine

Tricyclic antidepressants

Selegiline

Mirtazepine

Duloxetine

Fluvoxamine

Paroxetine

Gene Phenotype

CYP2C9 Normal metabolizer

CYP2C19 Ultra-rapid metabolizer

CYP2D6 Poor metabolizer

UGT2B15 Intermediate metabolizer

HTRA2A CC

HLA-B*15:02 Negative

HLA-A*31:01 Negative


Pharmacogenetics consult note

• Provide link between gene and drug

• Provide assessment considering additional patient

characteristics

• Provide recommendations for therapeutic modifications

as appropriate


Although a PGx report may be specific to a medication class

these results can frequently be applied to inform other therapies

CYP2C19

• Clopidogrel

• Citalopram

• Escitalopram

• Sertraline

• Voriconazole

• Tertiary amine

TCAs

CYP2C9

• Warfarin

• Phenytoin

CYP2D6

• Codeine

• Paroxetine

• Noritriptyline

• Fluovoxamine

• Ondansetron

• Tamoxifen

HLA-A

• Carbamazepine

HLA-B

• Carbamazepine

• Oxcarbazepine

Pharmacogenetics in practice


Enhance clinical

services


Increase patient

compliance

Decrease healthcare

costs


Improve dosing

algorithms

What do I do if my patient brings me a

direct to consumer test result?

Direct to consumer testing

Direct to consumer (DTC) test result

interpretation

• Patients can upload their raw DNA results to numerous third

party vendors for a “full interpretation” of their results

• Some focus on specific types of interpretations:

– Nutrition

– Medicine

– Fitness

• Very different formats for reporting results, levels of evidence,

and recommendations

• Highly variable cost and turnaround time

Common DTC report structures

• rsID interpretation

– Often list each variant individually with associated literature

– Interpretation or summary information often pulled directly from

SNPedia.com

A female patient uploads her DTC to a report generator.

She has a history of atrial fibrillation and is currently on

warfarin therapy. She has heard genetics is associated with

warfarin and she wants to see what her report says about

this drug.


Below highlights the results provided by the interpretation

engine for warfarin:

rsID Gene Result Summary

rs1799853 CYP2C9 C;C normal; no risk of altered

warfarin metabolism or NSAID

metabolism

rs1057910 CYP2C9 A;C CYP2C9*3 carrier; average

40% reduction in warfarin

metabolism

rs9923231 VKORC1 C;T reduced warfarin dose if treated

for VTE

Display of data adapted from SNPedia.com


Can condense and make sense of this data using the

previously described resources:

rsID Gene Result *allele Genotype Summary

rs1799853 CYP2C9 C;C *2 *1/*3 Initial reduced dose of warfarin recommended for

decreased metabolism and decreased sensitivity.rs1057910 CYP2C9 A;C *3

rs8050894 VKORC1 G;G NA CT


• Pathway interpretation

– Describe results related genes involved in a specific

metabolism or biological pathway

• May include all SNPs for that gene included on the platform or only

SNPs with strong evidence for association

• Does not always solve the problem of contradictory recommendations

Pathway RsID Result Gene Recommendation

Neurotransmission rs4680 AG COMT Avoid Methyl B12

Methylation rs1802059 AA MTRR Take Methyl B12

FDA approved DTC pharmacogenetic test

results

The report is approved to include the

following genes:

• CYP2C9

• CYP2C19

• CYP3A5

• UGT1A1

• DPYD

• TPMT

• SLCO1B1

• CYP2D6

“This report describes if a person has variants associated with metabolism of some

therapeutics, but does not describe if a person will or will not respond to a particular

therapeutic, and does not describe the association between detected variants and any

specific therapeutic. The PGS Pharmacogenetic Reports are not a substitute for visits

to a healthcare professional. The information provided by this report should not be

used to start, stop, or change any course of treatment.”- U.S. FDA

U.S. Food and Drug Administration, Center for Devices and Radiological Health. 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports, approval letter, October 31, 2018

Common DTC reports

E. Vessell, 1980s

Interpretation of Direct to Consumer tests

• These results can be informative but they can also cause

more confusion

• Can help to guide if additional confirmatory testing may

need to be considered

• Often do not provide a “composite phenotype” for

interpretation of multiple variants in the same gene

– Can make pharmacogenetic recommendations challenging

Summary

• Integration of pharmacogenetics has the potential to improve

patient care

• There are resource to described levels of evidence for drug-

gene relationships and provide treatment recommendation

for well-validated drug-gene pairs

• Direct to consumer tests can be informative but often have

variable interpretations

• All pharmacogenetic testing needs to be considered in the

context of the specific patient

Pharmacogenetic Testing: When Is It Useful and Why Might ... · What is pharmacogenetics? •The term pharmacogenetics commonly refers to the study of how variations in a single gene

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