PHARMACOGENOMICS AN INTRODUCTION TO PERSONALIZED MEDICINE

Megan Penner-Willis, PharmD

Clinical Assistant Professor

UAA/ISU Doctor of Pharmacy Program

DISCLOSURES

I do not have (nor does any immediate family member have)

a vested interest in or affiliation with any corporate

organization offering financial support or grant monies for

this continuing education activity, or any affiliation with an

organization whose philosophy could potentially bias my

presentation.

LEARNING OBJECTIVES

Pharmacists & Technicians

• Define pharmacogenomics

• Recognize and problem solve barriers to pharmacogenomic testing

Pharmacy Technicians • Identify potential role in

administering pharmacogenomic

tests

Pharmacists • Identify patients who may benefit

from pharmacogenomic testing

PHARMACOGENOMICS

The study of how genes impact a person’s response to medication

1. Exploring the use of Pharmacogenomic Testing in Primary Care for the Treatment of Depression and Anxiety | Mcubed. (n.d.). Retrieved January 5, 2020, from https://mcubed.umich.edu/projects/exploring-use-pharmacogenomic-testing-improve-depression-treatment-primary-care

THE MEDICATIONS

Over 200 medications have pharmacogenomic data listed in the package insert

Over 10% of medications in the top 200 drug list reference pharmacogenomics in the package insert

Over 20 different medication classes: analgesia, cardiology, HIV, oncology, psychiatry

THE ENZYMES

Pharmacogenomics Testing. (n.d.). Retrieved September 6, 2018, from http://www.tarnowcenter.com/integrative-psychiatry/29-tarnow-articles/integrative-psychiatry/433-pharmacogenomics-testing.html

many

more

G6PD

Cytochrome P450

CYTOCHROME P450

THE ENZYMES - METABOLISM

Pharmacogenomics Testing. (n.d.). Retrieved September 6, 2018, from http://www.tarnowcenter.com/integrative-psychiatry/29-tarnow-articles/integrative-psychiatry/433-pharmacogenomics-testing.html

Ultra-rapid Metabolizer

Low [Drug]

Extensive Metabolizer

Normal [Drug]

Intermediate Metabolizer

Variable [Drug]

Poor Metabolizer

High [Drug]

Inactive Drug Drug

Clopidogrel Active Drug

2C19

If a person is a 2C19 poor metabolizer, what would be the predicted

impact on clopidogrel concentrations?

a) Increase

b) Decrease

c) No change

Clopidogrel Active Drug

2C19

Risk

of

Stroke

Risk

of

Bleed

CLINICAL IMPACT

“Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic

Stroke or Transient Ischemic Attack”

• Up to 30% of the Caucasian population and 60% of the Eastern Asian

population has loss of CYP2C19 function alleles (*2, *3, *8)

• Statistically significant increased risk of stroke (12% vs 5.8%) and vascular

events (composite stroke, myocardial infarction, or vascular death: 13.7% vs

9.4%).

1. Pan Y, Chen W, Xu Y, Yi X, Han Y, Yang Q, Li X, Huang L, Johnston SC, Zhao X, Liu L, Zhang Q, Wang G, Wang Y, Wang Y. Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-

analysis.Circulation. 2017;135:21–33. doi: 10.1161/CIRCULATIONAHA.116.024913.

2. Simon, T., & Danchin, N. (2017). Clinical Impact of Pharmacogenomics of Clopidogrel in Stroke. Circulation, 135(1), 34-37. doi:10.1161/circulationaha.116.025198

PHARMACOGENOMICS RADAR

Neuro-psychiatric

Cardio-vascular

Pain Management

Oncology

HIV

PHARMACOGENOMICS DATA

SSRI’S – HOPE FOR LESS TRIAL AND ERROR?

• A cohort study of 1202 patients suggests sertraline dose

reductions of 60% and 25% in poor metabolizers and

intermediate metabolizers, respectively (Braten et al.,

2019).

• Additional studies provide dosing recommendations for

citalopram, escitalopram, fluvoxamine, and paroxetine

based on pharmacogenomic testing.

1. Bråten, L.S., Haslemo, T., Jukic, M.M. et al. Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients. Neuropsychopharmacol. (2019) doi:10.1038/s41386-019-0554-x

2. 1. Kaye, A. D., Garcia, A. J., Hall, O. M., Jeha, G. M., Cramer, K. D., Granier, A. L., … Urman, R. D. (2019). Update on the pharmacogenomics of pain management. Pharmacogenomics and personalized medicine, 12, 125–143. doi:10.2147/PGPM.S179152

GUIDED TRIAL

• Largest-ever pharmacogenomics-guided depression trial

• 1167 patients with major depressive disorder with at least

one previously failed depression medication

• Significant improvement in remission (15% vs 10%,

p=0.007) and response rates (26% vs 20%, p=0.013)with

pharmacogenomic-guided care versus standard care

1. Greden, J. F., Parikh, S. V., Rothschild, A. J., Thase, M. E., Dunlop, B. W., DeBattista, C., … Dechairo, B. (2019). Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. Journal of

Psychiatric Research, 111, 59–67. https://doi.org/10.1016/j.jpsychires.2019.01.003

COST SAVINGS IN MENTAL HEALTH TREATMENT

1. The Pharmacist’s Value in Pharmacogenetic Testing for Mental Health. (n.d.). Retrieved January 5, 2020, from Pharmacy Times website: https://www.pharmacytimes.com/publications/issue/2019/august2019/the-pharmacists-value-in-pharmacogenetic-testing-for-mental-health

PAIN MANAGEMENT

• Codeine: contraindicated in children <12 years due to risk

of respiratory depression from ultra-rapid metabolization

via CYP2D6

• Tramadol: prodrug also activated by CYP2D6

1. Kaye, A. D., Garcia, A. J., Hall, O. M., Jeha, G. M., Cramer, K. D., Granier, A. L., … Urman, R. D. (2019). Update on the pharmacogenomics of pain management. Pharmacogenomics and personalized medicine, 12, 125–143. doi:10.2147/PGPM.S179152

PAIN MANAGEMENT

• Fentanyl: no statistically significant findings for

polymorphism-related adverse events

• Hydrocodone: metabolized to hydromorphone via

CYP2D6

• Morphine: studies have demonstrated relationship between

polymorphisms and pain control, respiratory depression

1. Kaye, A. D., Garcia, A. J., Hall, O. M., Jeha, G. M., Cramer, K. D., Granier, A. L., … Urman, R. D. (2019). Update on the pharmacogenomics of pain management. Pharmacogenomics and personalized medicine, 12, 125–143. doi:10.2147/PGPM.S179152

CARDIOVASCULAR

• A randomized, open-label study of 2488 patients found in

patients undergoing PCI, a CYP2C19 genotype-guided

strategy for antiplatelet therapy was noninferior with

regards to thrombotic events and resulted in lower

incidence of bleeding (Claassens et al., 2019).

• There is evidence to support cost effectiveness of PGX

testing for clopidogrel and warfarin, but evidence is lacking

for other areas of cardiovascular care (Zhu et al., 2019).

1. Claassens, D. M. F., Vos, G. J. A., Bergmeijer, T. O., Hermanides, R. S., van ’t Hof, A. W. J., van der Harst, P., … ten Berg , J. M. (2019). A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI. New England Journal of Medicine, 381(17), 1621–1631.

https://doi.org/10.1056/NEJMoa1907096

2. Zhu, Y., Swanson, K.M., Rojas, R.L. et al. Systematic review of the evidence on the cost-effectiveness of pharmacogenomics-guided treatment for cardiovascular diseases. Genet Med (2019) doi:10.1038/s41436-019-0667-y

THE TEST

PHARMACOGENOMIC TESTING

Cheek swab

One time cost of

$150-400

1. The Utility of Pre-emptive Pharmacogenomic Testing. (n.d.). Retrieved January 5, 2020, from RxGenomix website:

https://www.rxgenomix.com/insight/the-utility-of-pre-emptive-pharmacogenomic-testing/

PHARMACOGENOMIC TESTING SUPPLIERS

• Genesight

• Geneticoncept

• MD Labs (Rxight)

• PharmacoDx

• RxGenomix

• SureGene

• Dozens more…

LIMITATIONS

FDA Stance: “The FDA is alerting patients and health care providers that claims for many genetic tests to predict a patient's response to specific medications have not been reviewed by the FDA, and may not have the scientific or clinical evidence to support this use for most medications. Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient.”

1. US Food and Drug Administration. The FDA Warns Against the Use of Many Genetic Tests With Unapproved Claims to Predict Patient Response to Specific Medications. https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-

claims-predict-patient-response-specific. Accessed December 30, 2019.

FDA APPROVAL

• “Direct-to-consumer”

• Requires statement that consumers should not use test

results to stop or change medications

• FDA approval = test is accurate and reproducible

APPLYING PGX TO PRACTICE

PHARMACOGENOMICS IN PRACTICE

Obtain Sample Review Results

with Patient

Contact Provider with

Recommendations

Community Pharmacy

PHARMACOGENOMICS IN PRACTICE

Obtain Sample Review Results

with Patient

Adjust Medications as Appropriate

Ambulatory Care

PHARMACOGENOMICS IN PRACTICE

Obtain Sample

Educate Patient and Provider on

Results

(if still admitted)

Adjust Medications

(if still admitted)

Inpatient

THE UNIVERSITY OF CHICAGO CENTER FOR

PERSONALIZED MEDICINE

Genomic Prescribing System

(GPS)

The University of Chicago Center for Personalized Therapeutics. (n.d.). Retrieved August 2, 2018, from https://cpt.uchicago.edu/

COVERAGE & REIMBURSEMENT

• October 2019 – United Healthcare started covering PGX

testing for patients diagnosed with anxiety and depression

whose medication(s) has failed

• Medicare can cover pharmacogenomic testing if deemed

medically necessary…

• Individual PGX suppliers provide reimbursement for

providing PGX education and consultation

1. Pharmacogenetic Testing. (2019). Retrieved from https://www.uhcprovider.com/content/dam/provider/docs/public/policies/comm-medical-drug/pharmacogenetic-testing.pdf

CHALLENGES

• Communication between care settings

• Cost

• Lack of reimbursement for administering and

interpreting results

APPLYING TO PRACTICE

What area of pharmacogenomics interests you or

would be most applicable to your practice site?

RESEARCH TO WATCH

• Million Veteran Program

• RIGHT 10K Study

• 1200 Patients Project

TRAINING & CERTIFICATE PROGRAMS

• American Society of Health-System Pharmacists

(ASHP)

• National Association of Chain Drug Stores

(NACDS) – Test2Learn

• University of Colorado

PHARMACOGENOMICS RESOURCES

• Clinical Pharmcogenetics Implementation

Consortium (CPIC) - cpicpgx.org

• PharmGKB - pharmgkb.org

PHARMACOGENOMICS AN INTRODUCTION TO PERSONALIZED MEDICINE

Megan Penner-Willis, PharmD

Clinical Assistant Professor

UAA/ISU Doctor of Pharmacy Program

pennmeg2@isu.edu