Utilizing Pharmacogenomics (PGx) in Pharmacy PracticeGarrett Aikens, PharmD, BCACP

2019 APA Annual ConventionSandestin, Florida

Disclosures

• There are no financial or other conflicts of interest to disclose

Objectives

1. Define pharmacogenomics (PGx) and how it can be used to guide individualized pharmacotherapy

2. Identify key resources for completing PGx testing, interpreting results, and referencing guideline recommendations

3. Interpret PGx testing results to provide patient specific pharmacotherapeutic recommendations

Factors impacting drug safety and efficacy

• Age• Gender• Ethnicity• Renal function• Hepatic function• Drug-drug interactions• Drug-disease interactions• Drug-food interactions• Drug-gene interactions

• Absorption

• Metabolism

• Clearance

Patient Case (renal function)

67 year old maleSCr 1.7 CrCl 38 ml/minHeight 5’8” (68”)Weight 165 lbs (75 kg)

Active Problems: HTN, Afib

Current Drugs: • Amlodipine• Carvedilol• Rivaroxaban

Decrease rivaroxaban dose to prevent supratherapeutic serum drug levels that could result from poor renal function

Patient Case (drug-drug interaction)

67 year old maleSCr 1.7 CrCl 38 ml/minHeight 5’8” (68”)Weight 165 lbs (75 kg)

Active Problems: HTN, Afib, skin infection

Current Drugs: • Amlodipine• Carvedilol• Warfarin

• New Drug:• SMX/TMP

Decrease warfarin dose to prevent supratherapeutic serum drug levels that could result from inhibition of warfarin metabolism by another drug

Patient Case (drug-gene interaction)

67 year old maleSCr 1.7 CrCl 38 ml/minHeight 5’8” (68”)Weight 165 lbs (75 kg)

Active Problems: HTN, recent MI

Current Drugs: • Lisinopril• Carvedilol• Clopidogrel

• PGx results: CYP2C19 Poor MetabolizerSwitch clopidogrel to an alternative to prevent subtherapeutic serum drug levels that could result from abnormal genetic makeup

Genetics and Health Care

• The Human Genome Project started in

• The goal of the Human Genome Project was to determine the full sequence of DNA and map all human genes to their physical and functional role

• The entire human genome was coded and mapped by

• We now know normal and variant gene types that cause genetic disorders including variants in genes that effect pharmacokinetics/pharmacodynamics

1990

2003

Pharmacogenomics (PGx)

• The study of how a person’s genetic make up affects that’s person’s response to drug therapy

• Improved drug efficacy

• Improved drug safety

• Decreased adverse drug effects

Accessed from http://rxpgx.com/about on 5/22/19

Pharmacogenomics (PGx)

• Cases of drug-gene interactions began surfacing as early as the 1950’s

• Some surgical patients experiencing prolonged effects and slower recovery times after succinylcholine administration

• Variations in N-acetyltransferase led to wide ranging serum concentrations of isoniazid and procainamide

Kalow W, et al. Can J Biochem Physiol. 1957;35:339-346Price-Evans DA, et al. Br Med J. 1960;2:485-491

Pharmacogenomics (PGx)

• We now know that variances in enzyme activity is determined by the allelic makeup of the genes

• The allelic makeup of genes can be extensive and complicated

• CYP2D6 has over 75 possible allelic variations

• The gene pairing (genotype) determines the activity (phenotype) of the enzymes associated with that gene

• CYP2C19• *1/*17 = Ultrarapid Metabolizer• *1/*1 = Normal (or Extensive) Metabolizer• *1/*2 = Intermediate Metabolizer• *2/*2 = Poor Metabolizer

Pharmacogenomics (PGx): rates of gene variants

CYP2C9 CYP2C19 CYP2D6

Ultrarapid Metabolizer N/A ~2 – 5% ~1 – 2%

Rapid Metabolizer N/A ~2 – 30% N/A

Normal Metabolizer ~91% ~35 – 50% ~77 – 92%

Intermediate Metabolizer ~8% ~18 – 45% ~2 – 11%

Poor Metabolizer ~1% ~2 – 15% ~5 – 10%

Caudle KE, et al. Clin Pharm Ther. 2014;96:542-548Hicks JK, et al. Clin Pharm Ther. 2017; 102:37-44

Common Drugs with PGx Testing Recommendations

• HLA-B*5701 allele screening is recommended for all patients prior to therapy due to the risk of a hypersensitivity reaction for patients with HLA-B*5701.

• Screening prior to treatment has been shown to decrease this risk

• Hypersensitivity causes a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following: fever, rash, GI, constitution, and resp

• Abacavir

Common Drugs with PGx Testing Recommendations

• HLA-B*1502 screening is recommended for patients of Asian descent due the high prevalence of this allele.

• The HLA-B*1502 allele has been linked to higher rates of toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) while taking carbamazepine

• Carbamazepine

Common Drugs with PGx Testing Recommendations

• Prodrug that is metabolized by CPY2C19 to the active metabolite.

• Patients who are homozygous for nonfunctional alleles (two non-functional alleles) of the CYP2C19 gene are poor metabolizers.

• 2% White• 4% Black• 14% Chinese

• CYP2C19 poor metabolizers should be switched to an alternative antiplatelet agent

• Clopidogrel

Pharmacogenomic Biomarkers in Drug Labeling

• The FDA provides a table of therapeutic products from with pharmacogenomic information found in the drug labeling

• The labeling for some, but not all, of the products includes specific actions to be taken based on the biomarker information

• https://www.fda.gov/drugs/science-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling

*CPIC: Drug-gene pairs listed with testing recommendations and/or potential actions required based on results

https://cpicpgx.org/genes-drugs/

From www.fda.gov

PGx Testing

• Who does it?• The Community Pharmacists Pharmacogenetics Network (CPPN) provides a

list of PGx labs included what type of PGx testing is performed and links to the labs online information: http://rxpgx.com/rxpgx-labs

• FDA approved direct-to-consumer testing in 2018 (23&Me®)

• Do they test all variants?• Some labs do not test all common and/or possible gene variants which may

lead to inaccurate PGx results

• How is it performed?• Most common specimen sources

• Buccal swabs• Blood samples

• Whole genome/exome sequencing (possible ethical concerns)• Single or Multi-gene testing

• Can be disease specific (i.e. psychiatric PGx panel)

PGx Testing (How is it reported?)

• Usually reported in color coordinated categories (“bins”)• Green: minimal drug-gene interaction (use normally)• Yellow: moderate drug-gene interaction (use with caution)• Red: major drug-gene interaction (avoid if possible)

• Categories may be based on efficacy and/or safety

• Recommendations should not be made on color category alone

• What pharmacodynamic or pharmacokinetic factors are effected and to what extent

PGx Testing (What is the pharmacist’s role?)

ASHP Position Statement• Recommending or scheduling PGx testing to aid in drug and

dosage selection.• Optimizing patient outcomes through designing a patient-

specific drug and dosage regimen based on the patient’s PGx profile that also considers:

• pharmacokinetic and pharmacodynamic properties of the drug• Comorbidities• other drug therapy• Demographics• laboratory data

• Educating patients, pharmacists, and other health care professionals about PGx principles

• Communicating PGx-specific drug therapy recommendations to the health care team

ASHP. Am J Health-Syst Pharm. 2015;72:579-581

PGx Metabolizer Definitions

• Ultrarapid Metabolizer (UM): Fastest metabolizer

• Rapid Metabolizer (RM): Faster than normal, but not the fastest

• Normal Metabolizer (sometimes called “extensive metabolizer”)

• Intermediate Metabolizer (IM): Slower than normal, but not the slowest

• Poor Metabolizer (PM): Slowest metabolizer

PGx Transporter Definitions

• Increased function: Increased transporter function compared to normal

• Normal function

• Decreased function: Decreased transporter function, but some function

• Poor function: Little to no transporter function

PGx Test Results

Gene Genotype PhenotypeCYP2D6 *2A/*2A Ultrarapid Metabolizer

CYP2C19 *1/*2 Intermediate Metabolizer

CYP2C9 *1/*1 Normal Metabolizer

CYP1A2 -163C>A – A/A Ultrarapid Metabolizer

SLC6A4 L/L High Activity

HTR2A G/G Reduced Activity

Inte

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tatio

n

Adapted from Winner JG, et al. Discov Med 2013;16:219-227

Enzyme (Gene) Genotype PhenotypeCYP2D6 *2A/*2A Ultrarapid Metabolizer

CYP2C19 *1/*2 Intermediate Metabolizer

CYP2C9 *1/*1 Normal Metabolizer

CYP1A2 -163C>A – A/A Ultrarapid Metabolizer

SLC6A4 L/L High Activity

HTR2A G/G Reduced Activity

PGx (Applying results to drug therapy)

• Not all results and labs are equal• Certain allele pairs may not be tested for • Some gene variants are only seen in specific people groups

• Some results/interpretations provided by a PGx lab may include recommendations on how to use/dose certain medications

• May not be based on strong evidence• Will not take into account drug-drug interactions

• Guidelines are available that utilize evidenced based dosing recommendations

• CPIC https://cpicpgx.org/• DPWG https://www.pharmgkb.org/page/dpwg• CPNDS https://www.pharmgkb.org/page/cpnds• PharmGKB https://www.pharmgkb.org/guidelineAnnotations

• compiles a table of all guidelines from multiple organizations

• In the absence of guidelines, remember your drug metabolisms, transporters, and receptors

PGx Resources: CPIC

• Clinical Pharmacogenetic Implementation Consortium (CPIC)

• Aims to overcome the barrier of translating PGx laboratory test results and developing actionable prescribing decisions for affected drugs

• Free, Peer-reviewed, Clinical practice guidelines for interpreting and applying PGx results

• Endorsed by the ASHP and ASCPT

Patient Case: Batman

• Batman is a 63 year old male with a history of HTN and Dyslipidemia that contributed to his MI several moths ago. Upon discharge from the hospital, Clopidogrel was added to his medication regimen to prevent a recurrent MI.

• PGx testing was not done at the time of clopidogrel initiation, but after learning about the impact that genetics can have on the effectiveness of clopidogrel, Batman decided to have a CYP2C19 genotype test done at his own expense. As his pharmacist (and most available health care provider) he brings in his results to you and asks for your recommendation(s).

Patient Case: Batman

Gene Genotype PhenotypeCYP2C19 *1/*1 Extensive Metabolizer

Use with CautionAvoid Use as Directed

Batman’s CYP2C19 genetic test results with phenotype interpretation

What category below would you place clopidogrel based on Batman’s genetic test results?

Clopidogrel

Patient Case: Joker

• Joker is a 63 year old male with a history of HTN and Dyslipidemia that contributed to his MI several moths ago. Upon discharge from the hospital, Clopidogrel was added to his medication regimen to prevent a recurrent MI.

• PGx testing was not done at the time of clopidogrel initiation, but after learning about the impact that genetics can have on the effectiveness of clopidogrel, Joker decided to have a CYP2C19 genotype test done at his own expense. As his pharmacist (and most available health care provider) he brings in his results to you and asks for your recommendation(s).

Patient Case: Joker

Gene Genotype PhenotypeCYP2C19 *1/*2 Intermediate Metabolizer

Use with CautionAvoid Use as Directed

Joker’s CYP2C19 genetic test results with phenotype interpretation

What category below would you place clopidogrel based on Joker’s genetic test results?

What recommendation would you make to Joker and his cardiologist?

CPIC Clopidogrel Guidelines

Phenotype (genotype) Implications for clopidogrel

Ultrarapid metabolizer (UM)Normal metabolizer

Normal or increased (UM) platelet inhibition; normal or decreased (UM) residual platelet aggregation

Clopidogrel: label-recommended dosage and administration

Intermediate metabolizer (IM)Reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events

Alternative antiplatelet therapy (if no contraindication), e.g. prasugrel, ticagrelor

Poor metabolizer (PM)

Significantly reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events

Alternative antiplatelet therapy (if no contraindication), e.g., prasugrel, ticagrelor

Scott SA, et al. Clin Pharmacol Ther 2013; 94(3):317-323

Patient Case: Joker

Gene Genotype PhenotypeCYP2C19 *1/*2 Intermediate Metabolizer

Use with CautionAvoid Use as Directed

Joker’s CYP2C19 genetic test results with phenotype interpretation

What category below would you place clopidogrel based on Joker’s genetic test results?

What recommendation would you make to Joker and his cardiologist?

Clopidogrel

Switch to an alternative agent such as prasugrel or ticagrelor

Patient Case: Wonder Woman

• Wonder Woman is a 38 year old female who has begun experiencing symptoms of depression and social anxiety. She is evaluated by a local psychiatrist confirms these diagnoses. Wonder Woman and psychiatrist agree to start antidepressant therapy, but would first like to perform pharmacogenetic testing to help in selecting an agent. The psychiatrist asks you for your recommendations based on the results of Wonder Woman’s PGx panel.

Patient Case: Wonder Woman

Gene Genotype PhenotypeCYP2D6 *1/*1 Normal Metabolizer

CYP2C19 *17/*17 Ultrarapid Metabolizer

SLC6A4 L/L Normal response to SSRIs

Moderate drug-gene interaction

Major drug-gene interaction

Minimal drug-gene interaction

Wonder Woman’s psychiatric genetic panel results with phenotype interpretation

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Patient Case: Wonder Woman (group discussion)

• What medication and dose would you recommend and why?

• What if the patient tries and does not tolerate desvenlafaxine?

Antidepressant Guidelines for CYP2C19

Gene Phenotype Drug response Guideline Recommendation

CYP2C19 Ultrarapid metabolizer

Increased metabolism of citalopram/escitalopram

CPICUse an alternative drug not predominantly metabolized by CYP2C19

DPGW

Titrate dose to a maximum of 150% in response to efficacy and adverse drug event, or select an alternative drug

Increased metabolism of tricyclic antidepressants (TCAs)

CPIC

Consider alternative drug not metabolized by CYP2C19

*May consider TCA metabolized to lesser extent (i.e. nortriptyline and desimpramine)

Scott SA, et al. Clin Pharmacol Ther 2013; 94(3):317-323

Patient Case: Wonder Woman (group discussion)

• What medication and dose would you recommend and why?

• What if the patient tries and does not tolerate desvenlafaxine?

PGx and Clinical Outcomes

Cardiology• IGNITE: Clopidogrel post PCI in CYP2C19 IM/PM patients

resulted in: • 2 fold increase in secondary events (95% CI 1.18-4.32)• 4 fold increase in death (95% CI 1.37-10.35)

• CYP2C19 IM/PM patients prescribed alternative therapy results in:

• Similar rates of secondary events compared to EM/UM patients of CYP2C19

Metal Health• PGx guided treatment significantly improves response rates

(p=0.001) and remission rates (p=0.02) at 12 weeks compared to usual care

Cavallari LH, et al. JACC Cardiovasc Inter 2018;11:181-191Lee CK, et al. Circ Genom Precis Med 2018;11:e002069

Bradley P, et al. J Psych Res. 2018;96:100-107

PGx (Looking forward)

• Diabetes• Tobacco Cessation• Pain Management• Hyperlipidemia• Cost-effectiveness• Integrating results into the

medical/pharmacy software to run drug-gene interaction checks

Key Takeaways

• PGx is becoming a common test that can further individualize medication regimens to improve patient outcomes

• Pharmacists are and will continue to play an important role in interpreting and applying PGx results

• Knowing how genetic variants effect drug metabolism and transportation is important, but other drug and patient factors must be considered

• Green, Yellow, and Red are a good start, but remember the old stuff

Questions and Discussion