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Pharmacogenomics and Improving Patient Care Rob Leffler, R.Ph 3/5/2019 Disclosure of Commercial Interests I have not consulted for and do not have financial interest in any organizations related to Pharmacogenomics. Rob Leffler is the Vice President of Clinical Services for PCA Pharmacy PCA Pharmacy is a provider of pharmacy services for Long-Term Care Facilities. Copyright 2019 PCA Pharmacy. 1 Pharmacogenomics and Improving Patient Care Rob Leffler, R.Ph. March 18, 2019 Copyright 2019 PCA Pharmacy. 2 Objectives • Identify what pharmacogenomic testing is and how it can be utilized • Describe how pharmacogenetic tests can inform prescribing decisions • Discuss pros and cons of pharmacogenetic testing • Identify patients that could benefit from pharmacogenomic testing • Explain why pharmacogenomic testing is valuable to another healthcare professional Copyright 2019 PCA Pharmacy. 3 1 3/5/2019 THANK YOU! • Dr. David Bright, PharmD, BCACP; Associate Professor at Ferris State University College of Pharmacy • Dr. David Kisor, BS, PharmD; Professor and Chair of Pharmaceutical Sciences; Director of Master of Science in Pharmacogenomics at Manchester University • Dr. Thomas Smith, Pharm.D., BCPP; Assistant Professor of Pharmacy Practice at Manchester University College of Pharmacy • Dr Shannon Zandy, Pharm.D., Ph.D., Medical Science Liaison at Myriad Genetics Copyright 2019 PCA Pharmacy. 4 One Drug Does Not Fit All Spear (2001) Trends Mol Medicine 7(5):201‐4. Copyright 2019 PCA Pharmacy. 5 5 Precision Medicine or Personalized Medicine • 2015 State of the Union Address announced the launch of the Precision Medicine Initiative • Isn’t medicine being personalized already? • Doses and drugs are selected based on other diagnoses, kidney function, etc. • Are therapeutic responses always predictable? • Are there still unanticipated side effects? • Genes can correlate to how well or even whether drugs work https://www.nih.gov/precision‐medicine‐initiative‐cohort‐program. Accessed 10/4/2016 Copyright 2019 PCA Pharmacy. 6 2 3/5/2019 Personalized Medicine • Provide the “right patient with the right drug at the right dose at the right time” • Genetic or protein biomarkers that may predict medication response or adverse effects • Pharmacogenomics • Subset of personalized medicine currently implemented in certain practice settings1 https://www.genome.gov/27530645/faq‐about‐pharmacogenomics/ 1 Relling and Evans (2015) Nature 526(7573):343‐50. Copyright 2019 PCA Pharmacy. 7 7 Precision Medicine or Personalized Medicine • Drugs are designed for the “average patient” • Drugs helped some people but not others • We ARE customizing drug selection based on personalized factors such as genetics, environment and lifestyle • We are NOT creating custom medications for individual patients • Ex: Huge advances have been made in the treatment of cancer • This initiative is constantly expanding to other drugs Kisor DF, et al. Pharmacogenetics, Kinetics, and Dynamics for Personalized Medicine. JBL 2013. Copyright 2019 PCA Pharmacy. 8 Example: • Cystic Fibrosis is the most commonly inherited disease in Caucasians • Affects 1 in 3,000 newborns • Carrier frequency is 1 in 25 • Certain cases are caused by a specific genetic mutation of CFTR modulators • This mutation can be treated with drugs: ivacaftor (Kalydeco) & lumacaftor/ivacaftor (Orkambi) https://www.ncbi.nlm.nih.gov/pubmed/12143267 https://www.ncbi.nlm.nih.gov/pubmed/19780730. Copyright 2019 PCA Pharmacy. Accessed 10/4/16 9 3 3/5/2019 Copyright 2019 PCA Pharmacy. 10 PGx/PGX and PGt • Genomics • Genome – Study of the entire DNA sequence • Pharmacogenomics (PGx or PGX) • Study of how a person’s genes affect a person’s response to particular drugs • More general term for the interface of genomics and therapeutics • Pharmacogenetics (PGt) • Study of how one gene affects a person’s response to a particular drug https://ghr.nlm.nih.gov/handbook/precisionmedicine/precisionvspersonalized Copyright 2019 PCA Pharmacy. 11 Genotype and Phenotype • Genotype: Genetic coding • Example: CYP2C19 GG (*1/*1) • Phenotype: Expression of genetic coding • Example: extensive (normal) metabolizer • Other Genotypes • *2 - G is replaced by A • *17 - C is replaced by T Copyright 2019 PCA Pharmacy. 12 4 3/5/2019 More Definitions • Single nucleotide polymorphism (SNP, pronounced “SNIP”): A variant DNA sequence in which a single nucleotide has been replaced by another base • cytosine (C), thymine (T), adenine (A), guanine (G) • These changes can impact transporters, receptors, metabolizing enzymes, etc. Copyright 2019 PCA Pharmacy. 13 Drug Metabolizing Enzymes • In pharmacogenomics, we are often concerned with SNPs in drug metabolizing enzymes in the liver • Examples: CYP450 2C9, 2C19, 2D6 • Many drugs are metabolized by the liver • More activity • Less activity Copyright 2019 PCA Pharmacy. 14 CYP2C19 SNPs • Common CYP2C19 alleles: • *1 (standard function) • *2, *3 (loss of function; no function) • *17 (gain of function) • One allele from each parent • Combinations of alleles must be considered to understand CYP function (Phenotype) • *17/*17 (ultra rapid metabolizer/UM) • *1/*1 (normal (extensive) metabolizer/EM) • *1/*2 ; *2/*17 (intermediate metabolizer/IM) • *2/*2 (poor metabolizer/PM) Scott SA, et al. Clin Pharmacol Ther 2013;94(3):317‐23. Copyright 2019 PCA Pharmacy. 15 5 3/5/2019 CYP2C19 SNPs • European/African ancestry: • ~30% express a *2 allele, 3-4% as *2/*2 • Oceanian ancestry: • ~61% express a *2 allele • Implications for drugs activated or inactivated by CYP2C19 Scott SA, et al. Clin Pharmacol Ther 2013;94(3):317‐23. Copyright 2019 PCA Pharmacy. Johnson JA, et al. Clin Pharmacol Ther 2012;91(5):774‐6. 16 Why Are We Concerned with Geriatrics? • Treating geriatric patients can be difficult due to polypharmacy • About 40% of geriatric patients are on ≥5 Rx medications1 • Long-term care residents take an average of 8.5 prescriptions on a regular basis2 • The prevalence and severity of adverse drug reactions (ADRs) is increased in older people • 5-10% of hospital admissions amongst older people are related to ADRs3 • Older people are 4x more likely to be admitted to hospital because of ADR (16.6% vs. 4.1%) and are more likely to have preventable ADRs (88% vs. 24%)4 1Qato (2008) JAMA 300(24):2867‐78. 2Stevenson (2014) Med Care 52(10):884‐90. 3Davies (2015) Br J Clin Pharmacol 80(4): 796‐807. 4Beijer (2002) Pharm World Sci 24(2):46‐54. Copyright 2019 PCA Pharmacy. 17 17 Why Are Adverse Drug Reactions Increased? • Comorbidities1,2 • Polypharmacy2 • Physiologic Changes2,3 • Pharmacokinetic changes • Pharmacodynamic changes Prescription drug use in the past 30 days, by number of drugs taken and age: United States 2007‐2010.4 1Nobili (2011) J Comorb 1:28‐44. 2Davies (2015) Br J Clin Pharmacol 80(4): 796‐807. 3Brunton (2018) Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed 4 th Katzung (2012) Basic and Clinical Pharmacology, 12 ed Copyright 2019 PCA Pharmacy. 18 18 6 3/5/2019 Pharmacokinetic Changes in the Elderly Absorption may be delayed, but bioavailability is largely unchanged1 Absorption Drugs with high 1st pass metabolism are an exception2 Fat ↑, highly lipophilic drugs may have longer half‐lives Distribution Water ↓, hydrophilic drugs may have higher concentraons2 Phase I: CYP450 enzyme acvity reported ↓ in elderly although conflicng reports3 Metabolism One study found patients age >70 CYP450 activity reduced by ~30%4 Phase II: Mostly conserved in the elderly population2 Reduction in kidney size, blood flow, nephron function, and filtration rate can lead Excretion to a decrease in elimination of water‐soluble drugs and/or metabolites5 1Jansen (2012) Scientifica (Cairo) 2012:723678 2Klotz (2009) Drug Metab Rev 41(2):67‐76. 3Tijiri (2013) World J Gastroenterol 19(46):8459‐67. 4Sotaniemi (1997) Clin Pharm Ther 61(3):331‐9. 5Katzung (2012) Basic and Clinical Pharmacology, 12th ed Copyright 2019 PCA Pharmacy. MISD.187.01.176 19 The Role of PGx in Geriatric ADRs • Frequently hospitalized older adults (≥65 yo) showed significantly higher frequency of PGx polymorphisms compared to matched older adults with polypharmacy rarely admitted to hospital1 • ≥3 hospital admissions in last 2 years and taking ≥5 medications • Limitation: 6 cases and 6 controls (nested case-control) • CYP450 substrates associated with greater readmission rates and greater healthcare costs2 • At discharge, at least one CYP450 substrate was associated with 10% increase in odds of 90- day readmission (OR of 1.104 in claims and 1.128 in EMR; P<0.001) • Substrates of CYP450 2D6 and 1A2 reported out individual risk in both cohorts • Any CYP450 substrate associated with increased monthly medical costs (+$397, p<0.003) 1Finkelstein (2016) Pharmacogenomics Pers Med 9:107‐116. 2 McCoy (2017) Pharmacogenomics J 17(4):382‐385. Copyright 2019 PCA Pharmacy. 20 20 PGx Clinical Applications GERMLINE & SOMATIC ONCOLOGY CARDIOLOGY CYSTIC FIBROSIS STATINS BRCA / LYNPARZA HER2 / HERCEPTIN CYP2C9 / WARFARIN CYP2D6 / TAMOXIFEN CFTR / KALYDECO SLCO1B1 / SIMVASTATIN VKORC1 / WARFARIN EGFR / ERBITUX 2C19 / CLOPIDOGREL BRAF / ZELBORAF PSYCHIATRY CYP2D6 / ARIPIPRAZOLE CYP2C19 / CITALOPRAM CYP2D6 / THIORIDAZINE CYP2D6 / VORTIOXETINE https://www.fda.gov/downloads/drugs/scienceresearch/ucm578588.pdf [FDA Table of Pharmacogenomic Biomarkers in Drug Labeling] https://cpicpgx.org/guidelines/ Copyright 2019 PCA Pharmacy. 21 7 3/5/2019 Cardiology • Heart Attack (Myocardial Infarction) • For a major heart attack, two primary treatment approaches: • Open-heart bypass surgery • Stent placement • After stent placement • Control blood pressure
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