Pharmacogenomics: An Introduction to an Opportunity

1. Pharmacogenomics: An Introduction to an Opportunity Sue Paul, RPh Co-Founder PGx101 LLC President SyneRxgy Consulting, LLC Co-Founder Medipreneurs LLC

2. Disclosure • Sue Paul, RPh is the President of SyneRxgy Consulting and co-Founder of PGx101 incorporating PGx services in practice. She has no financial disclosures.

3. To Discuss ways PGx testing and Personalized Medicine can improve prescribing • outcomes • Describe at least two resources that pharmacists can use to answer questions s specific to PGx To Define basic pharmacogenomic terminology To Discuss example case(s) To Describe PGx implementation into practice Objectives

4. “Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals.… What if figuring out the right dose of medicine was as simple as taking our temperature?”- President Obama, January 30, 2015 Precision Medicine Initiative The All of Us Research Program by the NIH seeks to extend precision medicine to all diseases by building a national research cohort of one million or more U.S. participants. Many factors have converged to make now the right time to begin a program of this scale and scope. https://allofus.nih.gov

6. Gene A sequence of nucleotides within a chromosome that act as instructions for protein synthesis 2% of the human genome are genes 20-30K genes are within the human genome <1% vary between people Genetic Concepts • Allele • Alternate forms or varieties of a gene • 2 Alleles ( one from each parent) • Together these alleles make up a genotype • Can be wild-type (common) or variant Genetics 101. The hereditary material of Life. Summer 2012 Issue. Volume 8 Number 2. Page 11-12. National Library of Medicine. US, Bestheda

7. Definitions DNA, Allele, Chromosome, Genotype, Phenotype

8. single nucleotide polymorphism (SNP) A variant DNA sequence in which a single nucleotide has been replaced by another base. Cells sometimes make mistakes during the copying process - kind of like typos. These typos lead to variations in the DNA sequence at particular locations, called single nucleotide polymorphisms, or SNPs (pronounced “snips"). SNPs cause polymorphisms if it is present in >1% of the population and a mutation if <1%. single nucleotide polymorphism (SNP) A variant DNA sequence in which a single nucleotide has been replaced by another base.

9. DefinitionsPharmacokinetics, Pharmacodynamics

10. Predictors for Drug Dosing • Age, weight, comorbidities and biochemical markers are commonly used to select an appropriate dose • Between 25-80% of patients respond beneficially to a given drug • $3.5 billion is spent on excess medical costs of adverse drug events annually • 10-17% of hospitalizations of older American related directly to adverse drug events • Drug tolerability issues are associated with poor medication adherence Pharmacogenomics could offer additional clinical decision support Spear BB1, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med. 2001 May;7(5):201-4. Institute of Medicine. Committee on Odentifying and Preventing Medical Errors. Preventing Medication Errors. Washington, DC: The national academic Press. 2006

11. Mortality Causes ~60% of meds in top 20 list of medications causing ADRs are linked to a genetic variation >150 drugs have labels with genetic information Lazarou et al. JAMA 1998; 279:1200-1205; Phillips KA et al JAMA 2001;286:2270-2279

12. Cytochrome P450 (CYP450) • Family of heme-proteins 450 (Pigment with an absorbance at 450nm) • Responsible for >80% of all Phase I drug metabolism in the liver & gut • 57 cytochrome P450s in humans

13. CYP Enzyme Polymorphisms

14. EM – Extensive Metabolizer -Normal- Heterozygous IM – Intermediate Metabolizer - Heterozygous PM – Poor Metabolizer - Homozygous UM – UltraRapid Metabolizer - Homozygous Opioid CYP2D6 Response

15. Risk Reduction Patient Improvement Cost Savings Therapies Benefiting from PGx Today Patient Satisfaction & Compliance

16. Benefits of PGx • Providers have more patient-specific list of medications to choose from • Patients are seeing better benefit:risk ratios from their medications • Reduced number of high acuity visits (ER visits and hospitalizations)

17. 73% of Patients had Drug-Gene Conflicts • 703 Patients, avg 12 med/pt, 4 meds/pt with genetic link • 28% Psychotropics • 32% CV-related • 20% Pain management • 20% Other (allergy/asthma, cough, nausea, etc) • 3,113 Combined drug-drug interactions 1 Brixner D, Biltaji E, Bress A, Unni S, Ye X, Mamiya T, et al. The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy. J Med Econ. 2016;19(3):213–28. doi: 10.3111/13696998.2015.1110160. pmid:26478982 2 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170905#abstract0

18. Savings • PGx testing reduced hospitalizations by 39% and ED visits by 79% for elderly patients1 • PGx testing performed on home health patients using multiple medications reduced hospital readmissions by 52% and ED visits by 42% 2 1 Brixner D, Biltaji E, Bress A, Unni S, Ye X, Mamiya T, et al. The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy. J Med Econ. 2016;19(3):213–28. doi: 10.3111/13696998.2015.1110160. pmid:26478982 2 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170905#abstract0

19. Website Resources • Clinical Pharmacogenomics Implementation Consortium (CPIC) • www.cpicpgx.org • Genetics/Genomics Competency Center (G2C2) • http://g-2-c-2.org • Pharmacogenomics Education Program (PharmGenEdTM) • http://pharmacogenomics.ucsd.edu • National Library of Medicine Genetics Home Reference • https://ghr.nlm.nih.gov • National Human Genome Research Institute • www.genome.gov/education • Pharmacogenomics Knowledgebase (PharmGKB) • www.pharmgkb.org • FDA “Table of Pharmacogenomic Biomarkers in Drug Labeling” • www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

20. Pharmacist Role in PGx Testing • APhA issued a white paper encouraging the development and integration of pharmacogenomics into pharmacy practice through MTM (2011) https://www.pharmacist.com/sites/default/files/files/mtm_integrating_pharmacogenomics.pdf • ASHP: Statement on the pharmacist’s role in clinical pharmacogenomics (2015) http://www.ashp.org/DocLibrary/BestPractices/SpecificStGenomics.aspx

21. Patient Case #1 JB 30 y.o. female PMH: dx depression, h/o heroin addiction, thyroid d.o., First step of recovery Medications at first encounter (8/2016): Lexapro, Rexulti (Brexpiprazole), Trazodone, Suboxone 6mg daily Genetic testing performed: LexaproRexulti Trazodone Homozygous for MTHFR enzyme deficiency Weaned Lexapro, add Wellbutrin, DC’d Rexulti, continued Trazodone PRN. Added L-Methylfolate 15mg daily. Current dose of Suboxone 1mg/0.25mg. (7/2018)

23. CLINICAL CONSIDERATIONS 2: Serum level may be too low, higher doses may be required. 4: Genotype may impact drug mechanism of action and result in reduced efficacy.

26. Patient Case #2 MK 60 y.o. WM resistant depression including daily SI Prior to testing Fluoxetine, Trazodone, (7/2016) Drinking 18-24 beers at night Gene testing performed Fluoxetine Trazodone Switched to Wellbutrin States he has his life back (12/2016) Has lost 50#, drinks socially on weekends only, and enjoys his old hobbies

27. Q & A