Houda Hachad, PharmD

PHARMACOGENOMICS IMPLEMENTATION: APPLICATION TO PEDIATRIC PATIENTS.

Disclosures Active Employee and equity holder of Translational Software, a technology company that build products to allow implementation of genomic medicine to the clinic

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Outline Introduction to Pharmacogenetics

Clinical Pharmacogenetics (PGX) Programs

Inova’s MediMap Program

Pediatric Pharmacogenetics

What we have learned so far

Conclusions

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Active Areas of Precision Medicine Targeted therapies for cancer

Pharmacogenomics (PGx)

Diagnosis and screening for constitutional disorders

Rapid identification of pathogens

Nutrigenomics and wellness

The microbiome

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Pharmacogenetics

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There is significant interpatient variability in drug response which is largely attributed to innate differences among individuals in their capacity to process and react to drugs.

Pharmacogenomics (PGx)

Study how genetics can be used to inform therapeutic decisions

Main goals is to “end the therapeutic odyssey”, lower the burden of adverse drug events and improve treatment outcomes

Novel tool to add to existing medication optimization tools such as therapeutic drug monitoring, medication therapy management approaches

PGx knowledge uses principles from human genetics, pharmacokinetics and pharmacodynamics

Issues revealed by PGx tests Inadequate exposure to active drug or metabolites

◦ Relates to Cytochrome P450 enzymes or transporters

◦ Linked to decreased or increased drug clearance associated with poor / fast metabolism or altered transporter function

◦ Metabolism phenotype range from poor (absent) to ultra-rapid (increased)

◦ Prodrug and active drug altered differently by metabolism phenotypes

Altered affinity of a drug for its target

◦ Altered expression of a drug target alters sensitivity to a drug

◦ Altered expression of a biological function

Idiosyncratic/immunological response

◦ Drug hypersensitivity reactions associated with HLA risk alleles

◦ Examples: Stevens-Johnson Syndrome and toxic epidermal necrolysis

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Examples of PGx applications Medication Gene - Type Issue Benefit

Codeine, Tramadol CYP2D6 (PK) Prodrug activation by CYP2D6

Loss of efficacy or increased toxicity Drug selection

Tricyclics, SSRIs CYP2C19 (PK) CYP2D6 (PK)

Inactivation of active drug by CYP2D6 and CYP2C19 Loss of efficacy or increased toxicity

Drug selection and dose optimization to avoid supra- or sub- therapeutic levels

Ondansetron CYP2D6 (PK) Inactivation of active drug by CYP2D6

Avoid loss of efficacy

Drug selection to avoid sub- therapeutic levels

Carbamazepine HLA-B*15:02 Hypersensitivity reaction in HLA risk allele carriers Drug selection

Warfarin CYP2C9 (PK) VKORC1 (PD)

Inactivation of active drug by CYP2C9-VKORC1 is warfarin target Decreased efficacy or increased toxicity

Adequate dosing requirements

Clopidogrel CYP2C19 – PK Prodrug activation by CYP2C19

Loss of efficacy or increased toxicity Drug selection

Thiopurines TPMT – PK Inactivation of active drug by TPMT

increased toxicity Dosing guidance to avoid toxicity

Atazanavir UGT1A1 - PK Inactivation of bilirubin by UGT1A1

Increased toxicity Drug selection

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Pharmaco genetic variability is multi-scalar

Single Gene and Single Variant

SLCO1B1 rs4149056 Simvastatin dosing

Single Gene and Multi- Variants

CYP2D6 rs16947 + rs3892097 + rs1065852

Opioids efficacy

Multi-Gene CYP2D6 + CYP2C19 Tricyclics, SSRIs dosing

Multi-Gene + other variables

CYP2C9 + VKORC1 + ethnicity

Warfarin dosing

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Consensus PGx Practice Guidelines

250 members from 30 countries

Experts from academia, hospitals, industry (FDA, NIH observers)

Practice guideline for 44 drug-genes pairs since 2010

In 2015 decision to consider pediatrics

https://cpicpgx.org/

PGx in the clinic: current landscape

PGX programs implemented in 45 healthcare institutions

International Consortia of Experts: CPIC – U-PGx – EUPIC

Regulator involvement (PGx Info In label)

Profusion of testing technologies and instrument vendors

Documented effectiveness of selected programs

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Institutions implementing PGx programs

BJC Healthcare Group Health / University of

Washington NorthShore University

HealthSystem University of Extremadura

Boston Children's Hospital / Harvard Medical

I.M.P. Institute of Predictive Medicine

Ohio State University University of Florida Health

British Columbia Pharmacy Association

Icahn School of Medicine at Mount Sinai

Robert-Bosch Stiftung University of Malta

Children's Cancer Hospital of Egypt

Indiana University Sanford Health University of Maryland

Children's Hospital Minnesota Inova Women’s Hospital Seattle Children's Hospital University of North Carolina

Cincinnati Children's Hospital Medical Center

Leiden University Medical Center St. Jude Children's Hospital University of Pennsylvania

School of Medicine

Clearview Cancer Institute Mayo Clinic Stanford University University of Pittsburgh / UPMC Presbyterian University Hospital

Cleveland Clinic Medical College of Wisconsin University Hospital Schleswig-Holstein

University of South Florida

CVS Caremark/Generation Health Mission Health University of Alabama Vanderbilt University

Erasmus MC Moffitt Cancer Center & Research Institute

University of Chicago Veterans Affairs

Geisinger Health System National Institutes of Health

Clinical Center (NIH CC) University of Colorado Washington University in St. Louis

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Institution Starting Date Genes Medications Reported Clinical Workflow Integration Technology Used

Boston Children’s Hospital InforMED Kids

2012 TPMT CYP2C9 VKORC1

Thiopurines Warfarin

The patient is swabbed and genotyped. Some of the genetic information is stored on the electronic patient’s medical records. BPAs exist for TPMT, CYP2C9, & VKORC1

EPIC/Cerner Affymetrix DMET+

Cincinnati Children’s Hospital

CYP2D6 CYP2C9 VKORC1

Psychotropic: Tricyclics and SSRIs Opioids Phenytoin Warfarin

Patient receives and fills out the test requisition form from the doctor. Patient also provides blood or cheek swabs for the lab. A report is generated with dosing recommendations, and drug-drug interactions. Pharmacology consults are available

Epic

St. Jude Children’s PG4KDs

2011 CYP2C19 CYP2D6 CYP3A5 DPYD SLCO1B1 TPMT UGT1A1 [230 genes assayed]

Clopidogrel Voriconazole Psychotropic: Tricyclics and SSRIs Opioids Tacrolimus Simvastatin Atazanavir Belinostat Thiopurines Dihydropyrimidines

Available to all patients Patient is enrolled, genotyped. Genotypes are evaluated and recorded in the medical records. Specific genotypes will send out BPAs when the doctor tries to order certain medications

Cerner Affymetrix DMET+

Inova MediMap

2016 TPMT CYP2C9 VKORC1 CYP2C19 SLCO1B1 CYP2D6 CYP3A5

Clopidogrel Tricyclics SSRIs Codeine Phenytoin Tacrolimus Simvastatin Thiopurines Voriconazole Ondansetron

Available to patients of Inova Buccal swab of patient is collected following consent Test run in-house An interpretive report is generated by Translational Software and delivered by genetic counselors to the parents A one time report that lives in the EMR

Epic Ion Torrent

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Inova’s PGx

Inova’s MediMap Baby • Offered to all newborns delivered at Inova Women’s Hospital and Inova Fair Oaks Hospital.

• Inova is the only health system in the U.S. that provides this optional PGx test to newborns free of charge as an optional part of the standard package of services.

•Multi disciplinary efforts between several partners

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https: https://www.inova.org/medimap/baby

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Inova’s MediMap Baby From a lab to the physician

Result

Files

Variant

Calls Type

Analysis Types

Meta-types

Phenotypes

Re

com

me

nd

atio

ns

Clinical

Report

Sample

acquisition

Lab test

Counselor/

Parents

EPIC

Counselor/

Parents

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Extending PGx Guidelines to Pediatrics CPIC guidelines are designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy not WHETHER tests should be ordered.

Developed primarily for adult patients from evidence-based review of studies in both adults and pediatric populations

Focus on FDA-approved indications and do not encompass all uses (off-label)

Assume full maturation of protein expression and function for the evaluated genes

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Applicability of PGx Guidelines to Pediatrics Pediatric pharmacogenetics requires a good understanding of:

clinical condition(s), demographic variability, approved use and off-label uses

the ontogeny (maturity projectory) of the genes and the impact of genetic variants on protein function/level

the interplay and the contribution of each of these confounding factors to the expected drug response variability

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Ontogeny analysis Review of studies documenting the development trajectory of protein encoded by tested genes

Limited availability of tissue samples (fetal and post-natal livers)

Some gene and protein function mature very early while others present a large variability during childhood (e.g CYP2C9)

Ontogenic CYP2C9 expression in the liver relative to adults. Dark blue columns represent population average. Light blue columns represent variability.

Hines RN. J Pharmacol Exp Ther. 2004 Mar;308(3):965-74.

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Maturation Trajectories Genes Maturation

TPMT, DPYD, VKORC1, CYP3A5 Fully mature at birth Remains constant

CYP2D6 Immature at birth

Increases rapidly to reach fully maturity within 4 weeks

CYP2C9, CYP2C19, SLCO1B1 Immature at birth

Increases progressively postnatally and during childhood to reach full maturity late childhood or at puberty – High variability

Limitation: level of expression of drug targets with or without variant are not well characterized during childhood, therefore the expression is assumed to be similar than the one in adults.

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Gene

Medication(s)

Evidence

Suitability

Notes

CYP2C19

Clopidogrel * yes but caution

Tricyclics/SSRIs * yes Indication dependent FDA Black-box in children

Voriconazole ** no - pediatric specific guidance

CYP2C9

Phenytoin ** yes but caution with specific pediatric dosing

Celecoxib ** yes with specific pediatric dosing

CYP2D6

Atomoxetine *** yes with specific pediatric dosing

Codeine *** yes but caution FDA Black-box in children

Ondansetron ** yes with specific pediatric dosing

Pimozide *** yes with specific pediatric dosing

Tricyclics/SSRIs * yes Indication dependent FDA Black-box in children

CYP3A5 Tacrolimus *** yes with specific pediatric dosing

DPYD Dihydropyrimidines *** yes

SLCO1B1 Simvastatin ** yes but caution

TPMT Thiopurines *** yes

CYP2C9/VKORC1 Warfarin *** no - pediatric specific guidance FDA Black-box in children

Adult PGx recommendations: suitability in Pediatrics

Medication for a child with sickle cell disease

Hand-foot syndrome, pain episodes ◦ opioids and non-opioid analgesics

Surgery: splenectomy ◦ antiemetics, Opioids

Allogenic stem cell transplant ◦ immunosupressants

Venous thromboembolism ◦ anticoagulants

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Conditions Which drug High risk group Issue

Hand-foot syndrome, pain episodes

Codeine CYP2D6 poor metabolizer CYP2D6 Ultra-rapid metabolizer

Lack or efficacy Life-threatening respiratory depression

Morphine OPRM1 altered function Higher dose requirement

Surgery: splenectomy Fentanyl, morphine OPRM1 altered function Higher dose requirement

Ondansetron CYP2D6 ultra-rapid metabolizer Lack of efficacy

Allogenic stem cell transplant

Tacrolimus CYP3A5 normal and intermediate metabolizers

Higher dose requirement

Venous thromboembolism

Warfarin CYP2C9 poor/intermediate metabolizer and/or VKORC1 decreased expression phenotype

Lower dose requirement

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PGx benefits for a child with sickle cell disease

Communicating Effectively Genetic test results are useless – understanding the implications is priceless

Alert on the consequences, not the genetic result

Tailor information to the audience – e.g. implications for the cardiologist, psychiatrist, or neurologist

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Clinician’s Curiosity is Limited by Time What we want to tell doctors

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What doctors want to know

Consider alternatives to Codeine #CYP2D6RapidMetabolizer

Interpreting and Reporting Results

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Gene Maturation Trajectories

What we have learned so far Inova’s MediMap program as an opportunity to screen a mostly healthy ethnically-diverse population and evaluate the uptake by families

Other PGx implementers within TSI network focuses on patients and mostly those that have comorbidities and likely to be polymedicated

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Inova’s Newborns with Actionable PGx

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3%

97% N= 8395

Non ActionablePhenotype

ActionablePhenotype

20.3

36.5

27.6

10.0

1.9

0.1

1

2

3

4

5

6

Nu

mb

er o

f ab

no

rmal

ph

eno

typ

es

Percentage of patients with one or more abnormal phenotype (s)

Genes Tested: CYP2D6, CYP2C9, CYP2C19, CYP3A5, SLCO1B1, VKORC1, TPMT

Medicated Patients with Actionable and Informative PGx

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69.51%

19.59%

10.90% Actionable

Informative

No PGx guidance

N = 563,000 - 93% had an abnormal phenotype for at least one of the tested genes

Genes Tested: CYP2D6, CYP2C9, CYP2C19, CYP3A5, SLCO1B1, VKORC1

Conclusions Rapid technological evolution is making genotype-guided prescribing attainable

PGx testing in children ◦ Despite limitation of extrapolating adult pharmacogenomics data to children, there are a number of

applications

◦ PGx information from adults is suitable with caution for Children in 75% of the cases and unclear in 25% of cases

◦ Current applications are highly informative when inadequate exposure is suspected

◦ A powerful tool that will allow us to consider pediatric patients as individual children

◦ Awareness and adoption of precision medicine is growing

◦ Focus on high value targets can accelerate adoption and diffusion

97% of Inova’s tested newborns are likely to benefit for PGx test

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Lifetime value of PGx testing

Neonates Infant Young Child Old Child - Adolescent Adult - Elderly

Surgery Coagulation Pain

Surgery Coagulation Pain

Surgery Coagulation Pain Psychiatry Transplantation Contraception

Surgery Coagulation Pain Psychiatry Transplantation Contraception Cardiovascular medicine Dementia

Medication Adverse Events Burden

Acknowledgements From Translational Software

◦ Hannah Rule and Jared Munir

From Inova Translational Medicine Institute (ITMI) ◦ Dr John Deeken, COO

◦ Dr Ramaswany Iyer, Director of the Institute’s laboratory: Inova Genomics Laboratory and Biobank

◦ Dr Natalie Hauser, Medical geneticist

◦ Allison Mitchell and Julie Muskett, Certified genetic counselors

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Contact me at houda.hachad@translationalsoftware.com