PHARMACOGENOMICS AN INTRODUCTION TO PERSONALIZED MEDICINE Megan - PowerPoint PPT Presentation

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 Pharmacists • Identify potential role in • Identify patients who may benefit administering pharmacogenomic from pharmacogenomic testing tests

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 many more G6PD Cytochrome P450 Pharmacogenomics Testing. (n.d.). Retrieved September 6, 2018, from http://www.tarnowcenter.com/integrative-psychiatry/29-tarnow-articles/integrative-psychiatry/433-pharmacogenomics-testing.html

CYTOCHROME P450

THE ENZYMES - METABOLISM Inactive Drug Drug Low [Drug] Normal [Drug] Variable [Drug] High [Drug] Ultra-rapid Extensive Intermediate Poor Metabolizer Metabolizer Metabolizer Metabolizer Pharmacogenomics Testing. (n.d.). Retrieved September 6, 2018, from http://www.tarnowcenter.com/integrative-psychiatry/29-tarnow-articles/integrative-psychiatry/433-pharmacogenomics-testing.html

Active Clopidogrel 2C19 Drug If a person is a 2C19 poor metabolizer, what would be the predicted impact on clopidogrel concentrations? a) Increase b) Decrease c) No change

Active Clopidogrel 2C19 Drug Risk Risk of of Stroke 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- HIV vascular Pain Oncology Management

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). Impac t 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 Time s 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 Community Pharmacy Contact Provider Review Results Obtain Sample with with Patient Recommendations

PHARMACOGENOMICS IN PRACTICE Ambulatory Care Adjust Review Results Obtain Sample Medications as with Patient Appropriate

PHARMACOGENOMICS IN PRACTICE Inpatient Educate Patient Adjust and Provider on Medications Obtain Sample Results (if still admitted) (if still admitted)

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/