Pharmacogenetics: Why some medications don t work - or make you feel worse - and what you can do about it.

Transcription

1 Pharmacogenetics: Why some medications don t work - or make you feel worse - and what you can do about it. Dan Doherty Senior Personalized Prescribing Consultant Genelex / YouScript April 2015 EDS NYC New York, NY

2 Disclosure / Acknowledgement Employed by Genelex/YouScript since 2006 Back ground in account management and social services Day-to-day operations include outreach to patients and physicians regarding pharmacogenetics. The Coalition Against Pediatric Pain & EDNF Long Island EDS Support Group & EDS NYC 2014 Genelex Corporation. All Rights Reserved.

3 Agenda: Overview of pharmacogenetics Phenotypes Pharmacogenetic data YouScript polypharmacy panel YouScript testing process What to do with your results YouScript online drug-gene interaction software demonstration Questions 2014 Genelex Corporation. All Rights Reserved.

4 4

5 Pharmacogenetics: Why some medications don t work - or make you feel worse - and what you can do about it. Dan Doherty Senior Personalized Prescribing Consultant Genelex / YouScript April 2015 EDS NYC New York, NY

6 6 Review so far 1. People do not respond to medication the same way. 2. We inherit our response to drugs.

7 7 Our best effort to impact drug response: Patient compliance! Taking the drug! Accordance to mealtimes! Accordance to sleep Drug/drug interactions! Inhibition! Induction Genetics! Pharmacogenetics

8 8 Pharmacogenetics Overview

9 Defining terms: Pharmacogenetics: the branch of pharmacology concerned with the effect of genetic factors on reactions to drugs. Allele: one of a pair of genes (one from mom, one from dad). Together your alleles determine your ezymatic capability and your phenotype. Alleles often appear as a number followed by a star: *1/*1, *1/*4, *2/*4, *1/*17, etc. Source: Gerloff, T, Implications of Pharmacogenetics in Every-Day Practice, Genelex Corporation. All Rights Reserved.

10 Defining terms: ADEs and ADRs Adverse drug event (ADE): An injury which results from drug use. Adverse drug reaction (ADR): A type of ADE that occurs when the drug is noxious, is unintended and occurs at doses normally used in man. Depending on the drug, an ADR can appear in many different forms, not limited to the below: Anxiety Brian fog Dizziness Forgetfulness Headache GI problems Seizure Abnormal behavior Source: Verbeurgt, P; How Common Are Drug and Gene Interactions, Genelex Corporation. All Rights Reserved.

11 Defining terms: DDI, DGI & DDGI Drug-drug interaction (DDI): A major cause of ADRs and can be divided into two categories: Pharmacodynamic: occurs when one drug modulates another drug s effects on the body. The effects can be additive, antagonistic or synergistic. Pharmacokinetic: occurs when one drug impacts the absorption, distribution, metabolism or excretion of another drug. This results in increased or decreased concentrations of one or both of the drugs. The CYP450 (CYPs), a family of enzymes responsible for the biotransformation of drugs, are a major cause of pharmacokinetic DDI s. Drug-gene interaction (DGI): A drug gene interaction occurs when a patient's genetic CYP450 type (e.g., CYP2D6 poor metabolizer) affects that patient's ability to clear a drug. Drug-drug-gene interaction (DDGI): A drug drug gene interaction occurs when the patient's CYP450 genotype and another drug in the patient's regimen (e.g., a CYP2D6 inhibitor) affect that individual's ability to clear a drug. Source: Verbeurgt, P; How Common Are Drug and Gene Interactions, Genelex Corporation. All Rights Reserved.

12 Pharmacogenetic Drug-Gene Interaction: Patients with inherited enzyme deficiencies are at risk to accumulate excessive drug concentrations when treated with standard doses which may lead to adverse drug reactions or even to life-threatening conditions. Source: Gerloff, T, Implications of Pharmacogenetics in Every-Day Practice, Genelex Corporation. All Rights Reserved.

13 13 Pharmacogenetic Phenotypes

14 Without genetics Advertised dose With genetics Personalized dose

15 Drug metabolism phenotypes Poor Metabolizer XX - (Non functioning allele) - (Non functioning allele) CYP2D6: 5.1% CYP2C9: 3.4% CYP2C19*: 2.3% Intermediate Metabolizer Normal Metabolizer - (Functioning allele) - (Non functioning allele) - (Functioning allele) - (Functioning allele) CYP2D6: 36% CYP2C9: 28.2% CYP2C19: 25.4% <25% of patients are normal for all three enzymes Rapid and Ultra Rapid Metabolizer - (Three or more functioning alleles) CYP2D6: 3.5% CYP2C9: N/A CYP2C19: 27.7% Source: Genelex Internal Data of approximately 13,000 patients *Frequencies may vary based on ethnicity

16 16 Normal Metabolizer Has two functioning alleles Can take medications at recommended FDA dosage as made by the pharmaceutical company Can still have allergies or side effects with meds

17 17 Intermediate Metabolizer Has one functioning allele and one non functioning allele These individuals make less enzyme than normal metabolizers Active drugs: drug exposure will typically increase so a lower dose may be appropriate Pro drugs: active metabolite will potentially decrease so a higher dose may be appropriate

18 18 Poor Metabolizer Has no functioning alleles These individuals make little to no enzyme Active drugs: very likely drug accumulation and potential risk of toxicity - drug level may increase significantly so a lower dose or alternate drug may be appropriate Pro drugs: potential lack of efficacy - active metabolite may not reach blood stream so an alternate drug may be appropriate

19 19 Rapid/Ultra Rapid Metabolizer Has more than two functioning alleles These individuals make more enzyme than normal metabolizers Active drugs: potential lack of efficacy - drug level may decrease so an increase of dose may be appropriate Pro drugs: potential risk drug accumulation and toxicity too much of the active metabolite may reach the blood stream so an alternate drug may be appropriate

20 20 Genetics affect drug clearance, leading to a range of response; from non-response to toxicity Illustration of a typical direct acting drug. Pro-drugs would have inverse curves. Drug Levels Toxic level Therapeutic level Drug Response Day PM: Poor Metabolizer IM: Intermediate Metabolizer EM: Extensive (normal) Metabolizer UM: Ultra Metabolizer PM IM EM UM 2014 Genelex Corporation. All Rights Reserved.

21 A single person can have different combinations of CYP450 results 2D6 PM 2C19 RM For this individual: Prozac would likely accumulate and potentially make them feel worse Prilosec would likely have a lack of efficacy at standard dose 2C9 NM 3A4 IM Motrin would likely provide pain relief at standard dose Advair would increase and would warrant monitoring for adverse effects

22 22 Pharmacogenetic Data

23 ADEs: Avoidable medical problem 700, , , , , , ,000 0 Heart Disease Cancer Stroke Rx Car Crashes 2.2 MILLION severe adverse drug reactions per year FOURTH leading cause of death in the U.S. 100,000 deaths per year by properly prescribed drugs 80,000 deaths per year by improperly prescribed drugs COST LEADER for malpractice payouts Sources: U.S. Center for Disease Control and Prevention and Journal of the American Medical Association (JAMA) 2014 Genelex Corporation. All Rights Reserved.

24 Study: How common are drug and gene interactions? Drug-gene interactions and drug-drug-gene interactions accounted for 33.9% of adverse drug events individuals with known 2D6, 2C9 and 2C19 genotypes. A total of 1053 major or substantial interactions were identified in 501 individuals. Drug-drug interactions (DDIs) accounted for 66.1% of interactions. Drug-gene interactions (DGIs) accounted for 14.7% of interactions. Drug-drug-gene interactions (DDGI) accounted for 19.2% of interactions. Source: Verbeurgt, P; How Common Are Drug and Gene Interactions, Genelex Corporation. All Rights Reserved.

25 25 More than 100 medications have drug-gene interactions identified by FDA in package insert A substantial portion involve three cytochromes: 2D6, 2C19, 2C9 Number of drugs with drug-gene labeling Other - 31 CYP2C19 13 CYP2C9 3 Commonly prescribed agents with drug-gene interactions listed in package insert 9 2D6: Abilify, Anafranil, Clozaril, Coreg, Detrol, Elavil, Evoxac, Fanapt, Lopressor, Luvox, Mellaril, Norpramin, Nuedexta, Provigil, Pamelor, Razadyne, Risperdal, Rythmol, Sinequan, Strattera, Tamoxifen, Tofranil, Trilafon, Ultram, Xenazine Oncology - 35 CYP2D6-36 Total: 118 drugs 2C19: Aciphex, Celexa, Dexilant, Nexium, Onfi, Plavix, Protonix, Sinequan, Soma, Valium 2C9: Warfarin, Celebrex, Ansaid 2014 Genelex Corporation. All Rights Reserved.

26 26 Cytochrome variants impact more patients than common genetic disorder testing Condition Genetic Test # Sufferers Source Cystic fibrosis CF Carrier Test 1:31 people or 30,000 US / 70,000 WW 1000 babies born each year Breast cancer BRCA 1 & 2 1:8 women, 1:1000 men 210,203 women in 2008 Only 15% are linked to BRCA 1 & 2 tests Downs syndrome Amniocentesis 1:691 births 400,000 US Cytochrome genetic variation Polypharmacy Psychiatric medications Cardio medications Pain medications CYP2D6 CYP2C19 CYP2C9 CYP2D6 CYP2C19 CYP2C9 CYP2D6 CYP2C19 CYP2D6 CYP2C19 CYP2D6 CYP2C19 CYP2C9 86% of US population 30 million US Estimated 14M are 65+ Most widely prescribed drugs 15% US men (est. 46M) 26% US women (est. 81M) 25% of top 200 drugs Most popularly prescribed drugs 209.5M prescriptions in 2010 Cystic Fibrosis Foundation BreastCancer.org National Down Syndrome Society Genelex 14k+ patients 100s published reference papers Administration on Aging, CVS Pharmacy Wall Street Journal / Medco Health Solutions Centers for Disease Control 2014 Genelex Corporation. All Rights Reserved.

27 27 YouScript Polypharmacy Panel: Enzymes: 2D6, 2C19, 2C9, 3A4, 3A5

28 Potential reasons for bad reactions to drugs: allergy non compliance genetic side effect (meals/sleep schedule) (general)

29 genetic CYP450 enzymes CYP 2D6 CYP 2C19 CYP 2C9 CYP 3A4 CYP 3A5

30 93% of tested patients have at least one of the five enzymes functioning differently than normal.

31 YouScript polypharmacy test panel The YouScript polypharmacy test panel looks at five enzymes: CYP 2D6, 2C19, 2C9, 3A4, 3A5 Large amount of clinically significant genetic variability between individuals. Metabolize 60-75% of all medications. Medicines most commonly associated with ADE are 8X more likely to use these enzymes Genelex Corporation. All Rights Reserved.

32 Some typical medications prescribed to patients in the Chiari/ Hypermobile/EDS population dependent on the CYP450 enzymes: Ondansetron Diazepam Cyclobenzaprine Ibuprofen Oxycodone Promethazine Alprazolam Diphenhydramine Metoprolol Duloxetine Escitalopram Amphetimine/Dextroamphetamine Tramadol Buproprion Midodrone Carisoprodol Hydrocodone Desogen Zolpidem Carvedilol Amitriptyline Fluoxetine

33 33 Testing process Order testing online: TEST-DNA

34 34 Painless Buccal Swab Collection

35 35 Test Requisition Form: Practitioner Portion

36 36 Test Requisition Form: Current Medications

37 37 Mail swabs and test requisition form to lab Results are received by your physician within 5 business days of Genelex receiving your sample. Patient wallet cards take two weeks.

38 Study An anonymous, cross-sectional, national pharmacogenetics survey of over 10,300 physicians was conducted in 2012: 97.6% of responding physicians agreed that genetic variations may influence drug response. Only 29.0% of physicians overall had received any education in the field. Only 12.9% of physicians had ordered a test in the previous 6 months. Only 10.3% felt adequately informed about pharmacogenomic testing. Source: Stanek EJ, Adoption of Pharmacogenetic Testing by US Physicians Genelex Corporation. All Rights Reserved.

39 39 Predictive Preventive Personalized Participatory

40 YouScript insurance coverage & billing " Medicare pays in full " Medicare Advantage may have lab testing co-pays ($20) " Private insurance covers 70% time; coverage varies depending on plan. " Generous Genelex billing policy We always appeal denials We do not balance bill Patient assistance program Based on income level 12 monthly payments 2014 Genelex Corporation. All Rights Reserved.

41 41 Results

42 42 Patient report: wallet card Wallet card includes online drug-gene interaction software at free for 90 days. Continued use thereafter is optional for $23.95 per year.

43 43 Physician report: phenotypes

44 44 Physician report: PharmD prescribing suggestions

45 45 Pharmacogenetics is a piece of the puzzle Sometimes it s the answer Fatigue Pain Genetics Allergies Pharmacogenetics Psychological Factors Medication side-effects Medical Conditions Diet & Exercise sometimes it s not.

46 46 One Physician s Perspective on Pharmacogenetics Pharmacogenetic testing can be invaluable in explaining past adverse medication reactions and in maximizing the likelihood of success and minimizing the risk of adverse reactions for future medication choices. Not all patients and not all medications will behave as rules of pharmacogentics or as data in the medical literature suggest, because everyone s different! - Alan Pocinki, MD TCAPP think tank Sept 2014

47 47 What to do with your results

48 48 What to do with your results: Provide a copy to all of your current and future healthcare providers. Start using the YouScript drug-gene interaction software at home. Always consult a physician prior to making any changes.

49 49 YouScript makes it easy to factor pharmacogenetics into prescribing decisions C B D A Multi-drug interactions C B D C A Drug-gene interactions A YouScript comprehensive medication management: Systems approach to multidrug interactions Addresses the cumulative impact of Drug B, C, D on Drug A Predicts drug-gene interactions Provides what-if scenarios and simplifies alternative selection Multi-drug-gene interactions 2014 Genelex Corporation. All Rights Reserved.

50 50 YouScript software is the most advanced medication management software available " Most comprehensive drug-gene and drug-drug interaction software 2,700 drugs & metabolites 11,500 clinical interaction notes 12,000 PubMed references & product inserts New data updated daily " Population Risk Analysis " Ranked Alternate Selector " Incorporates herbals, over-the-counter and recreational drugs " Genotype-based drug and dosage recommendations " Only solution to factor multi-drug and cumulative effects " EHR integration Allscripts TM Open App Challenge Winner 2014 Genelex Corporation. All Rights Reserved.

51 51 YouScript Demonstration

52 52 Questions? YouScript Personalized Prescribing System