Putting Pharmacogenomics into Practice · 1. Provide an overview of pharmacogenomics, including defining key terms and discussing its history 2. Summarize the current state of pharmacogenomics

Clinical Drug Information

Putting

Pharmacogenomics

into Practice

Brought to you by

Wolters Kluwer

Clinical Drug

Information

Daniel Streetman

Sherri J. Willard Argyres


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Wolters Kluwer Clinical Drug Information


Daniel Streetman, PharmD, MS

• Pharmacotherapy Specialist in the Metabolism, Interactions, and

Genomics Group for Wolters Kluwer Clinical Drug Information

• Prior to coming to Wolters Kluwer, Dr. Streetman was a clinical

faculty member at the University of Michigan for nearly eight years.

Dr. Streetman received his PharmD from Ohio Northern University

and a master's degree in clinical research design and statistical

analysis from the School of Public Health at the University of

Michigan and has completed a pharmacy practice residency and a

research fellowship in clinical pharmacology, with emphasis in

pharmacogenomics.

• He is accredited in Applied Pharmacology by the American Board of

Clinical Pharmacology, serves as a reviewer and editor for several

professional journals, and has authored more than 20 publications.


Sherri J. Willard Argyres, MA, PharmD, BCPS

• Medical science pharmacist for Wolters Kluwer Clinical Drug

Information and a clinical pharmacist for the Drug Use Research and

Management program at Oregon State University/Oregon Health and

Science University.

• She has seven years of research experience in molecular biology,

which she largely gained as a Harvard University graduate student in

the Department of Molecular Biology at Massachusetts General

Hospital. Dr. Willard Argyres holds a Doctor of Pharmacy degree from

Oregon State University/Oregon Health and Science University,

Master of Arts degree in microbiology and molecular genetics from

Harvard University, and post-graduate certificate in science

communications from the University of California at Santa Cruz.


1. Provide an overview of pharmacogenomics, including defining key

terms and discussing its history

2. Summarize the current state of pharmacogenomics in guidelines and

labeling

3. Describe components necessary to translate genetic information into

clinical action

4. Describe successes in the clinical implementation of

pharmacogenetics

Learning Objectives

CONFIDENTIAL AND PRIVILEGED. FOR INFORMATIONAL PURPOSES ONLY.


What is pharmacogenetics, and

why should I care?



0

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DBQ 4-OH DBQ Ratio

% E

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0 1 2 3 4 5 6 7

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mm

Hg)

Hours Post-DBQ

Hypotension following Debrisoquine

*Symptomatic hypotension in

all 3 PMs but no EMs

Maghoub A, et al. Lancet 1977;2:584-6. Idle JR, et al. Life Sci 1978;22:979-83.

CONFIDENTIAL AND

PRIVILEGED. FOR

INFORMATIONAL

PURPOSES ONLY.


Codeine and respiratory failure (CYP2D6)1,2,3,4,5,6

Fluoxetine fatality (CYP2D6)7

Azathioprine and fatal myelosuppression (TPMT)8

Phenytoin toxicity (CYP2C9)9

Other Significant Reports

1. Kelly LE, et al. Pediatrics 2012;129(5):e1343-7. 2. Ciszkowski C, et al. N Engl J Med 2009;361(8):827-8.

3. Voronov P, et al. Paediatr Anaesth 2007;17(7):684-7. 4. Koren G, et al. Lancet 2006;368(9536):704.

5. Gasche Y, et al. N Engl J Med 2004;351(27):2827-31. 6. Madadi P, et al. Can Fam Physician 2007;53(1):

33-5. 7. Sallee FR, et al. J Child Adolesc Psychopharmacol 2000;10:27-34. 8. Schütz E, et al. Lancet

1993;341(8842):436. 9. Brandolese R, et al. Clin Pharmacol Ther 2001;70(4):391-4.



1950s

– Isoniazid-associated polyneuritis (acetylation status; NAT1-2)

– Hemolysis following primaquine (G6PD deficiency)

– Prolonged apnea after succinylcholine (cholinesterase deficiency)

1959: Pharmacogenetics

"Study of the relationship between individual gene

variants and variable drug effects."

Early History: Neuritis, Hemolysis, and Apnea



1970s thru 1990s

– Many more sensitive drugs identified

– Underlying mechanism in slower and rapid metabolizers

– Standardized nomenclature

1997: Pharmacogenomics

"Study of the relationship between variants in a large collection of

genes, up to the entire genome, and variable drug effects."

Growing understanding and interest



CYP2D6 Variability

0

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25

30

Nu

mb

er

of

Pe

op

le

Enzyme Activity

Relling & Dervieux. Nature Reviews 2001;1:99-108.

CONFIDENTIAL AND

PRIVILEGED. FOR

INFORMATIONAL

PURPOSES ONLY.


Completion of Human Genome Project

– HapMap, SNP database

Explosion of related fields

– Epigenetics, Proteomics, Bioinformatics, etc.

Technology improvements

– Point-of-care testing, Decreased cost

Advances in understanding and technology

Dewey FE, et al. Phased whole-genome genetic risk in a family quartet

using a major allele reference sequence. PLoS Genet

2011;7(9):e1002280. Mother and daughter: CYP2C19 *17/*17

4 drugs more likely to work; 4 others less likely to work

Dose requirements like for 3 drugs



USA, Europe, Japan

– When PGx studies should be performed; Conduct and interpretation

of PGx studies; Banking of DNA encouraged

Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a

marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-

carvedilol compared to extensive metabolizers. Retrospective analysis of side effects in clinical trials

showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably

resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.

[Prescribing information. Coreg CR (carvedilol). Research Triangle Park, NC: GlaxoSmithKline; January 2011.]

CERDELGA is indicated for the long-term treatment of adult patients with Gaucher disease type 1

(GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor

metabolizers (PMs) as detected by an FDA-cleared test. Patients who are CYP2D6 ultra-rapid

metabolizers (URMs) may not achieve adequate concentrations of CERDELGA to achieve a therapeutic

effect. A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot

be determined.

[Prescribing information. Cerdelga (eliglustat). Waterford, Ireland: Genzyme Ireland, Ltd.; August 2014.]

Regulatory guidance



Personalized Medicine Coalition

– represents innovators, scientists,

patients, providers and payers

– promotes personalized medicine

concepts, services and products

Clinical Pharmacogenetics

Implementation Consortium (CPIC)

– Collaboration between PharmGKB and

Pharmacogenomics Research Consortium

– Remove some barriers to

implementation of PGx knowledge

– How information to be used, not

whether tests should be ordered

"I want the country that eliminated polio

and mapped the human genome to lead a

new era of medicine ... Tonight, I’m

launching a new Precision Medicine

Initiative to bring us closer to curing

diseases like cancer and diabetes -- and to

give all of us access to the personalized

information we need to keep ourselves

and our families healthier."

President Obama on personalized medicine

State of the Union Address

Jan. 20, 2015

Putting it all into practice

www.personalizedmedicinecoalition.org

www.pharmgkb.org/page/cpic



Where are we today with

respect to pharmacogenetics?



Lagging behind ...

Pharmacogenomics Knowledge

Clinical

Implementation



Predictions about the role

of PGx a bit too optimistic – (2002) By 2010, more than half of

drugs will have corresponding test

Many limitations

– Education

– Validity/Utility

– Reliability of testing

– Cost-effectiveness

– Legal, ethical issues 0

10

20

30

40

50

60

CurrentlyOffering

No Plans toOffer

% R

esp

onse

s

CYP

UGT1A1

Are we implementing too slowly?

Watson K et al. IVD Technology 2002;11:33.

Washington G-2 Reports' 2006 Molecular Diagnostic Test Survey.

CONFIDENTIAL AND

PRIVILEGED. FOR

INFORMATIONAL

PURPOSES ONLY.


0

200

400

600

800

1000

1200

1400

1600

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20001970-1

974

1975-1

979

1980-1

984

1985-1

989

1990

1991

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1997

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1999

2000

2001

2002

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2004

2005

2006

2007

2008

2009

2010

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2012

2013

2014

Publicati

ons

Surge in Pharmacogenetics and

Pharmacogenomics Literature

www.ncbi.nlm.nih.gov/pubmed (accessed 4/14/15)



US: >134 labels with PGx information (vs. 76 in 2004)

– CYP2D6 (36); G6PD (19)

– EMA: approximately 15% with data relevant to patient care

Few examples where labeling requires testing

– Eliglustat

CYP2D6 EMs or IMs: 84 mg BID; CYP2D6 PMs: 84 mg QD

– Carbamazepine

"Patients with ancestry in genetically at-risk populations should be

screened for ... HLA-B*1502 prior to initiating treatment..."

– Abacavir

"Prior to initiating therapy with abacavir, screening for the HLA-

B*5701 allele is recommended ..."

Pharmacogenetics in Labeling

www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

Ehmann F, et al. Br J Clin Pharmacol 2014;77:612-7. CONFIDENTIAL AND PRIVILEGED. FOR INFORMATIONAL PURPOSES ONLY.


Drug Gene(s) Group(s)

Abacavir HLA-B CPIC

Allopurinol HLA-B CPIC

Amitriptyline CYP2C19, 2D6 CPIC

Azathioprine TPMT CPIC

Boceprevir IFNL3 CPIC

Capecitabine DPYD CPIC

Carbamazepine HLA-B CPIC

Clomipramine CYP2C19, 2D6 CPIC

Clopidogrel CYP2C19 CPIC, AHA

Codeine CYP2D6 CPIC

Desipramine CYP2D6 CPIC

Doxepin CYP2C19, 2D6 CPIC

Fluorouracil DPYD CPIC

Imipramine CYP2C19, 2D6 CPIC

Interferons IFNL3 CPIC

Irinotecan UGT1A1 EGAPP

Drug Gene(s) Group(s)

Ivacaftor CFTR CPIC

Mercaptopurine DPYD CPIC

Nortriptyline CYP2D6 CPIC

Phenytoin CYP2C9, HLA-B CPIC

Rasburicase G6PD CPIC

Ribavirin IFNL3 CPIC

Simvastatin SLCO1B1 CPIC

SSRIs CYP2D6 EGAPP

Tacrolimus CYP3A5 CPIC

Tamoxifen CYP2D6 ACMG

Tegafur DPYD CPIC

Telaprevir IFNL3 CPIC

Thioguanine TPMT CPIC

Trimipramine CYP2C19, 2D6 CPIC

Warfarin CYP2C9, VKORC1 CPIC, ACMG

Royal Dutch Guidelines: 53 drugs, 11 genes

Published Guidelines

www.pharmgkb.org/view/dosing-guidelines.do?source=CPIC# Abul-Husn NS, et al. Pharmgenomics Pers Med 2014;7:227-40.

Swen JJ, et al. Clin Pharmacol Ther 2011;89:662-73. CONFIDENTIAL AND PRIVILEGED. FOR INFORMATIONAL PURPOSES ONLY.


St Jude Children's Hospital (PG4KDS)1

Vanderbilt University (PREDICT)2

University of Florida3,4

University of Chicago5

Mt Sinai Medical Center (BioMe program; CLIPMERGE-PGx)6

Coriell Institute for Medical Research

University of Maryland (PAP3)7

Mayo Clinic (RIGHT protocol)8

Indiana Institute of Personalized Medicine9

eMERGE-PGx (multicenter)10

Personalized Medicine Programs

1. Hoffman JM, et al. Am J Med Genet C Semin Med Genet 2014;166C:45-55. 2. Pulley JM, et al. Clin Pharmacol Ther

2012;92:87-95. 3. Weitzel KW, et al. Am J Med Genet C Semin Med Genet 2014;166C:56-67. 4. Johnson JA, et al.

Pharmacogenomics 2013;14(7):723-6. 5. O'Donnell PH, et al. Am J Med Genet C Semin Med Genet 2014;166C:68-755. 6.

Gottesman O, et al. Clin Pharmacol Ther 2013;94:214-7. 7. Shuldiner AR, et al. Am J Med Genet C Semin Med Genet

2014;166C(1):76-84. 8. Bielinski SJ, et al. Mayo Clin Proc 2014;89:25-33. 9. Levy KD, et al. Clin Pharmacol Ther

2014;96:307-9. 10. Rasmussen-Torvik LJ, et al. Clin Pharmacol Ther 2014;96(4):482-9.



Clinical

Implementation

of

Pharmacogenetics

Brought to you by

Wolters Kluwer

Clinical Drug

Information

April 21, 2015

Sherri J. Willard Argyres


Define clinical implementation of pharmacogenetics

Provide a sample description of the systematic process of implementing a

preemptive genotyping program

Identify the components necessary to translate pharmacogenetics into

clinical action

Identify stakeholders in providing educational resources

Provide examples of potential pharmacogenetic associations that have been

validated or investigated

Provide examples of educational and clinical support tools

Outline



The incorporation of pharmacogenetics into routine clinical

care by developing and implementing processes to perform

and interpret pharmacogenetic tests for variants that have

been clinically validated —adapted from Mary Relling

Definition: Clinical Implementation of PG



Sample preemptive PG program “process”

Analyze processes and perform drug

utilization review

Evaluate clinical evidence of PG

association

Build tables to translate

genotype into phenotype

Adapted from U of Florida. References for preemptive genotyping programs at end of slides.

CONFIDENTIAL AND

PRIVILEGED. FOR

INFORMATIONAL

PURPOSES ONLY.


Develop CDS and integrate

into EMR

Obtain approvals

Educate staff



Launch program

Adjudicate patient results

Evaluate programmatic

outcomes



Characteristics of ideal PG educational resource

Johansen Taber KA, Dickinson BD. Pharmacogenomic knowledge gaps and educational resource

needs among physicians in selected specialties. Pharmgenomics Pers Med. 2014;7:145-162



The selection of clinically actionable gene-drug associations for

implementation

The availability of commercially available pharmacogenetic tests

The interpretation of pharmacogenetic tests

The development of educational and clinical decision support tools

Components of translating PG into clinical action



FDA Biomarker list:

http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetic

s/ucm083378.htm

Prescribing information

Pharmacogenetic consortia guidelines, such as the Clinical Pharmacogenetic

Implementation Consortium (CPIC): https://www.pharmgkb.org/

Medical guidelines provided by professional societies and specialist

organizations

Research literature, published in journals as well as documentation part of

FDA drug approvals

Companies who specialize in providing clinical information

Identifying clinically actionable pharmacogenes


http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm



https://www.pharmgkb.org/


Genetic Testing Registry: http://www.ncbi.nlm.nih.gov/gtr/

The laboratory should be able to provide information about:

– The indication for ordering the test

– The variants tested

– The limitations of the test

– Not only analytic sensitivity and specificity but also the clinical sensitivity and

specificity of the test

Note: For tests, such as those for metabolizing enzymes, clinical sensitivity and specificity in

laboratory documentation refers to the ability to identify, for example, metabolizer status. For

example, a test for CYP2D6 metabolizer status will be able to classify >95% of Caucasians as

PM, EM, IM, or UM (ie, sensitivity of 95%). But this says nothing about the test’s ability to

correctly determine a safety or efficacy outcome.

Selection of pharmacogenetic tests



Transparent test results that indicate

– the subject’s genotype

– whether the variant of interest was detected

– translate the genotype to a drug-associated predictive phenotype, eg,

HLA-B*57:01 allele-abacavir detected: increased risk for hypersensitivity

CYP2D6 diplotype (combinations of functional, nonfunctional, decreased function, and

increased function alleles) phenotypes: poor, intermediate, extensive, and ultrarapid

metabolizer

– Note: These are not always consistently defined. This affects interpretation and

transportability of genetic testing information, so it’s important to have the genotype

accompany the phenotype.



Pharmacogenetic consortia guidelines

Medical guidelines provided by professional societies and specialist

organizations

Companies providing clinical information-enabled tools and software

solutions

Prescribing information

Health insurance companies

Laboratories

Resources for interpretation of PG tests



Based on a review of the literature and the reason for testing, an assessment

of the

– Evidence of association (clinical validity)

– Evidence of testing benefit (clinical utility)

Recommendations for whether or not to test (in reactive testing)

Clinical recommendations, including a variety of options

– For example, choice of another medication, choice of alternate dosing, phenotyping,

monitoring, not recommended for action

Elements of interpretation



Cancer pharmacogenes

– Targeted therapies for somatic cell mutations, eg,

BRAF-tyrosine kinase inhibitors (eg, melanoma)

ALK-crizotinib (eg, non-small cell lung cancer)

– Biomarkers predictive of efficacy, eg,

KRAS-cetuximab (eg, colorectal cancer)

Disease causing germline mutations with targeted therapies

– CFTR-ivacaftor (cystic fibrosis)

Genetic mutations for targeted therapies



Predict efficacy, eg,

– CYP2C19-clopidogrel (PCI)

– CYP2D6-tamoxifen (breast cancer)

– CYP2D6-codeine (pain management)

Predict adverse events, eg,

– HLA-B*57:01-abacavir (SJS/TEN)

– HLA-B*15:02-carbamazepine (SJS/TEN)

– SLCO1B1-simvastatin (myopathy)

– UGT1A1-pazopanib (hyperbilirubinemia)

“Normal” germline variants

CONFIDENTIAL AND PRIVILEGED. FOR INFORMATIONAL

PURPOSES ONLY.


Genotype-guided dosing, eg,

– CYP2B6-efavirenz (HIV)

– CYP2C19-clobazam (Lennox-Gastaut syndrome seizures)

– CPY2D6-eliglustat (Gaucher disease)

– CYP2D6-iloperidone (schizophrenia)

– CYP2D6-vortioxetine (MDD)

– CYP2C9/VKORC1-warfarin (thromboembolism)

– TPMT-thiopurines (cancer, IBS, rheumatoid arthritis, etc)

– UGT1A1-belinostat (T-cell lymphoma)

CONFIDENTIAL AND PRIVILEGED. FOR

INFORMATIONAL PURPOSES ONLY.


Precautions database

– A look-up tool, much like a drug-drug interaction checker

Referential information

– A monograph providing clinical recommendations, pharmacogenetic test

interpretation, ratings, supporting literature, and background information

Electronic Health Records into which clinical support tools have been

integrated

Educational and Clinical Support Tools



Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics

Program (TPP):

Goal is to translate widely accepted actionable pharmacogenetic discoveries into real-world

clinical practice

– University of Florida: Personalized Medicine Program

Weitzel KW, Elsey AR, Langaee TY, et al. Clinical pharmacogenetics implementation:

approaches, successes, and challenges. Am J Med Genet C Semin Med Genet. 2014;166C(1):56-

67

– Vanderbilt University: PREDICT

Pulley JM, Denny JC, Peterson JF, et al. Operational implementation of prospective genotyping

for personalized medicine: the design of the Vanderbilt PREDICT project. Clin. Pharmacol.

Ther. 2012;92(1):87-95

– University of Maryland: Personalized Anti-Platelet Pharmacogenetics Program

Shuldiner AR, Palmer K, Pakyz RE, et al. Implementation of pharmacogenetics: the University of

Maryland Personalized Anti-platelet Pharmacogenetics Program. Am J Med Genet C Semin Med

Genet. 2014;166C(1):76-84

Preemptive PG testing program references



– St. Jude’s Children’s Research Hospital: PG4KDS

Hoffman JM, Haidar CE, Wilkinson MR, et al. PG4KDS: a model for the clinical implementation

of pre-emptive pharmacogenetics. Am J Med Genet C Semin Med Genet. 2014;166C(1):45-55

– Mayo Clinic: RIGHT Protocol

Bielinski SJ, Olson JE, Pathak J, et al. Preemptive genotyping for personalized medicine: design

of the right drug, right dose, right time-using genomic data to individualize treatment

protocol. Mayo Clin. Proc. 2014;89(1):25-33

eMERGE-PGx Project

Rasmussen-Torvik LJ, Stallings SC, Gordon AS, et al. Design and anticipated outcomes of the

eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic

health record systems. Clin. Pharmacol. Ther. 2014;96(4):482-489

University of Chicago: 1200 Patients Project

O'Donnell PH, Danahey K, Jacobs M, et al. Adoption of a clinical pharmacogenomics

implementation program during outpatient care--initial results of the University of Chicago

"1,200 Patients Project". Am J Med Genet C Semin Med Genet. 2014;166C(1):68-75

Preemptive PG testing program references



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Documents

Putting Pharmacogenomics into Practice · 1. Provide an overview of pharmacogenomics, including defining key terms and discussing its history 2. Summarize the current state of pharmacogenomics