Genetic Testing Applications to Patient Care

Transcription

1 Genetic Testing Applications to Patient Care Roy E. Smith, MD Addiction Medicine Disclosure Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing health care goods or services related to the content of this CME activity. My content will include discussion/ reference to commercial products or services. I do not intend to discuss unapproved/ investigational use of commercial products or services. 1 2 Name Commercial Interests Genetic Testing Roy E Smith, MD September 2015 Relevant Financial Relationships: What Was Received Relevant Financial Relationships: For What Role Roy Smith MD No None None None No Relevant Financial Relationships with Any Commercial Interests Learning Objectives Discuss in general what this available genetic testing is and what its not. Demonstrate examples of the laboratory reports and the information contained in them Demonstrate how this newer laboratory testing is used to make clinical decisions Discuss some of the studies and literature behind the technology ( time permitting) 4 Key Points CYP450 liver enzymes Receptor characteristics Quality of reports depends on quality of information submitted Does not tell us that a medicine will or will not work. Helps tailor personalized medicine More rapidly treat depression / addiction 5 Clinical Use The Clinical Pharmacogenetics Implementation Consortium (CPIC) was created in 2009 to identify genetic druggene associations that have strong clinical evidence, and to publish guidelines that specify clinical actions based on those genetic test results

2 Know thy Patient It is more important to know what sort of person has a disease than to know what sort of disease a person has. -Hippocrates (460 BC 370 BC) Know thy Terminology Pharmacogenomics The general study of all genes that determine drug behavior including genes involved in: Ø How our body interacts with drugs (pharmacokinetics) Ø How drugs interact with our body (pharmacodynamics) Pharmacogenetics A subset of pharmacogenomics The study of inherited differences (variation) in drug response and metabolism Terms are used interchangeably Promise of Genomic Medicine Brief History of Pharmacogenetics BEFORE: Trial and error, One-dose-fits all AFTER: Personalized medicine (from genotype to phenotype) Ethnicity associated with differences in metabolic traits 1 NIH funds pharmacogenetics research 2 ~3000 genetic tests (and counting!) commercially available 5 No response Full response Partial response Toxicity Variations in adverse effects attributed to enzyme deficiencies 1 Effects of CYP450 polymorphism appear in literature 1 First genetic test is approved 4 DRUG A 100 mg DRUG A 500 mg DRUG A 10 mg Full human genome is mapped 3 ~50% respond 100% respond h#p:// 1. Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology with emphasis on cytochrome P450. Toxicol Sci. 2011;120(1): National Institutes of Health. Pharmacogenetics Research Network and Knowledge Base. Released April 7, RFA: GM Accessed April 12, Landau R, Bollag LA, Kraft JC. Pharmacogenetics and anaesthesia: the value of genetic profiling. Anaesthesia. 2012;67(2): US Department of Health and Human Services, US Food and Drug Administration. Device approvals and clearances. Updated June Accessed April 13, Leslie T, Agar D, Fielding S, Miller S. Booze Allen Hamilton Market Trends in Genetic Services Report (2012) 10 Addiction vs Other Chronic Diseases Disease Heritability Billion $ Addictions Alzheimer + dementias Pain (w migraine) Head and spinal cord injury Anxiety disorders Schizophrenia Depressive illness Developmental disorders Stroke Parkinson disease Multiple sclerosis Seizures Huntington disease Uhl and Grow (2004) Arch Gen Psychiatry 61: Millennium Laboratories, Inc. Working Model: Genetic Architecture of Substance Disorders Current working model of genetic architecture of substance dependence in general population includes: Substantial overall genetic influences Polygenic (multi-gene) architecture with small effects at each locus Potentially additive gene effects Environment Crabbe JC. Gene8c contribu8ons to addici8on. Annu. Rev. Psychol : Genetic loci 2014 Millennium Laboratories, 12 Inc. 2

3 Dopamine and Addiction Addiction Changes the Brain But So Does Recovery Addiction is All About the Dopamine - Nora Volkow, Director, National Institute on Drug Abuse Most drugs of abuse activate the dopaminergic system directly or indirectly Dopamine is involved in mediating positive (pleasurable) acute effects of many drugs as well as reinforcing behaviors leading to addiction Simon LH, Simon HLT. Clinical toxicology of newer recrea8onal drugs. Clin Toxicology. 2011;49: Na8onal Ins8tutes of Health, Na8onal Ins8tute on Drug Abuse. The Essence of Drug Addic8on Millennium Laboratories, 13 h#ps://science.educa8on.nih.gov/supplements/nih2/addic8on/guide/essence.htm Accessed April 24, Inc. PET image showing levels of dopamine transporters (DAT) in the striatal region of the brain as an indicator of dopamine system function. The METH abuser (center) shows greatly reduced levels of DAT (yellow and green), which return to nearly normal following prolonged abstinence (red and yellow). Image obtained from Na8onal Ins8tutes of Health, Na8onal Ins8tute on Drug Abuse. The Essence of Drug Addic8on Millennium Laboratories, 14 h#ps://science.educa8on.nih.gov/supplements/nih2/addic8on/guide/essence.htm Accessed April 24, Permission granted to use image for classroom educa8on ac8vi8es. Volkow, N.D., et al Journal of Neuroscience 21: Inc. Heritability Studies FINDINGS FROM STUDIES Studies evaluating addiction heritability typically involve analysis of families or twin studies These classical approaches examine co-occurrence or comorbidity of addictive traits in monozygotic vs dizygotic twins, reared together or apart, and in analogous family studies with other sorts of biological relatives These studies have provided solid evidence of genetic influence on addictions Twin studies specifically have demonstrated significant genetic impact on dependence of alcohol 1, cannabis 2, cocaine 3, nicotine 4 and polysubstance dependence 5, Millennium Laboratories, Inc Dick et al 2006 Ann Clin Psychiatry 18: Agrawal 2006 Addic8on 101, Agrawal et al (2004) American Journal of Medical Gene8cs Part B (Neuropsychiatric Gene8cs) 129B: Swan et al (1996) Journal of Substance Abuse 8: Kendler et al (2007) Arch Gen Psychiatry 64: Kendler et al (2006) Psychol Med. 36: Millennium Laboratories, Inc. What it is What it is. What it is not. Report of the genes that control Liver enzymes that metabolize meds.. Receptors for dopamine, serotonin, and some opiate receptors Receptors on Immune system cells How our body metabolizes Folate (B9)

4 What it is not. What it is not A full chromosomal analysis Saved for other analysis ( past 30 days) Added to gene data banks Used for paternity testing etc Some Key Gene Targets Cytochrome P450 Enzymes Dopamine Receptors Other Dopamine Pathway Components Dopamine transporter (DAT1) Dopmaine metabolizing enzyme (DBH, MAO-A) Opioid System (OPRM1) Serotonin Transporter Nicotinic Acetylcholine Receptor CYP450 Liver enzymes that metabolize many meds Substrates Inducers Inhibitors CYP2D6 CYP2C19 UGT2B15 Prodrug or Active Metabolite? Crabbe JC. Gene8c contribu8ons to addici8on. Annu. Rev. Psychol : Millennium Laboratories, Inc. 22 Pharmacogenetics and Antidepressants Clinical responses vary widely among individuals In STAR-D, after an average of 10 weeks of treatment and 5 visits to their healthcare provider, the remission rate was 27.5% 1 After treatment failure with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant 2 Pharmacogenetic differences may impact patient response to antidepressants CYP 450 enzymes commonly involved CYP2D6 and CYP2C19 MTHFR differences associated with decreased L-methylfolate 1. Trivedi levels M, Rush J and et al. Evalua8on depression of Outcomes with Citalopram risk 3 for Depression using Measurement- based Care in STAR*D: Implica8ons for Clinical Prac8ce. Am J Psychiatry. 2006; 163: Rush J, Trivedi M et al. Buproprion- SR, Sertraline, or Venlafaxine- XR aeer failure of SSRIs for depression. N Engl J Med. 2006; 354: Papakostas GI, Shelton RC, Zajecka JM, et al. L- Methylfolate as Adjunc8ve Therapy for SSRI- Resistant 2015 Major Millennium Depression: Results Health, of Two Randomized, LLC Double- Blind, Parallel- Sequen8al Trials. Am J Psychiatry. 2012;169: Dietary Folate, Folic Acid Variability in Medication Response Folate Deficiency & Depression MTHFR L-methylfolate Biologically active Affects NE, DA, 5HT synthesis Ginsberg L, et al. L- methylfolate plus SSRI or SNRI from Treatment Ini8a8on Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innov Clin 24 Neurosci. 2011;8(1) Millennium Health, LLC 4

5 SSRI/SNRI MTHFR Drug-Gene Pair Three Possible Clinical Phenotypes Greatly Reduced Activity Greatly reduced metabolism of folic acid into L-methylfolate 1 Supplementation with L-methylfolate may improve SSRI/SNRI response 2 Reduced Activity Decreased metabolism of folic acid into L-methylfolate 1 Supplementation with L-methylfolate may improve SSRI/SNRI response 2 Normal Activity Normal metabolism of folic acid into L- methylfolate 1 MTHFR For MTHFR ~50-60% of individuals have reduced or greatly reduced activity 3 1. Nazki FH, Sameer AS, Ganaie BA. Folate: Metabolism, genes, polymorphisms and the associated diseases. Gene. 2014;533: Papakostas GI, Shelton RC, Zajecka JM, et al. L- Methylfolate as Adjunc8ve Therapy for SSRI- Resistant Major Depression: Results of Two Randomized, Double- Blind, Parallel- Sequen8al Trials. Am J Psychiatry. 2012;169: Bo#o LD, Yang Q. 5,10- Methylenetetrahydrofolate Reductase Gene Variants and Congenital 2015 Anomalies: Millennium A HuGE Review. Health, Am J LLC Epidemiol. 2000;151(9): Patient Depression

6 CYP450 Case: Mike yo M, history of substance use disorder, including injecting opioids, heroin and abusing benzodiazepines PMH generalized anxiety disorder, hypertension, insomnia Current medication regimen: Methadone 60 mg PO daily Sertraline 100 mg PO daily Clonidine 0.1 mg PO BID Trazadone 100 mg PO daily 2015 Millennium Health, LLC 32 Case: Mike (cont) Finished a residential 30 day medication-assisted treatment program; starting an intensive outpatient program Upon admission to IOP, clinician orders PGT as part of comprehensive evaluation Orders: CYP2B6 for methadone CYP2D6, CYP2C19, MTHFR for antidepressants 2015 Millennium Health, LLC 33 Methadone Pharmacokinetics (R)- methadone CYP3A4 EDDP (inactive metabolite) (R): Primarily responsible for Mu(µ) opioid receptor effects CYP2B6 EDDP (S)- (inactive metabolite) methadone (S): Associated with cardiotoxic effects, specifically QT prolongation CYP2B6 demonstrates stereoselectivity in favor of metabolizing the (S)-enantiomer Gerber JG, Rhodes RJ, Gal J. Stereoselec8ve metabolism of methadone N- demethyla8on by cytochrome P4502B6 and 2C Chirality Jan;16(1): Millennium Health, LLC Case: Mike PGT Results Gene Tested Predicted Phenotype CYP2D6 Poor Metabolizer (PM) CYP2C19 Extensive (normal) Metabolizer CYP2B6 Poor Metabolizer (PM) MTHFR Potential Clinical Normal Consequences Activity for Methadone: 2015 Millennium Health, LLC 35 Case: Mike Interpretation CYP2B6 poor metabolism would result in increased concentration of (S)-methadone 1-2 Increased (S)-methadone levels may increase potential for toxicity, including QT prolongation 3-4 Variant alleles of CYP2B6 associated with higher plasma methadone concentrations 5 May require a reduced methadone dose for effective treatment of opioid dependence 5,6 1. Cre#ol S et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther. 2006;80(6): Cre#ol S et al. Methadone enan8omer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78(6): Eap CB et al. Stereoselec8ve block of herg channel by (S)- methadone and QT interval prolonga8on in CYP2B6 slow metabolizers. Clin Pharmacol Ther May;81(5): Bunten H et al. OPRM1 and CYP2B6 Gene Variants as Risk Factors in Methadone- Related Deaths. Clin Pharm & Ther. 2010;88(3): Gadel S, Crafford A, Regina K, Kharasch ED. Methadone N- demethyla8on by the common CYP2B6 allelic variant CYP2B6.6. Drug Metab Dispos. Apr 2013;41(4): Levran O, Peles E, Hamon S, Randesi M, Adelson M, Kreek MJ. CYP2B6 SNPs are associated with methadone dose required for effec8ve treatment of opioid addic8on. Addict Biol. Jul 2013;18(4): Millennium Health, LLC 36 6

7 OPRM1 37 Case: Karen 28 yo F, history of substance use disorder, drug of choice is alcohol; no other PMH Several DUIs, first drink at age 12 3 rd time in inpatient treatment facility, this time voluntary; recently tapered off chlordiazepoxide for withdrawal Motivated to stay sober and has been attending AA meetings and talk therapy Clinician would like to start oral naltrexone, orders PGT 2015 Millennium Health, LLC 38 Naltrexone and OPRM1 Naltrexone works by blocking Mu(µ) opioid receptors in the brain Agonist Binding Receptor Antagonist Binding Clinically Actionable PGT Naltrexone - OPRM1 Two clinical phenotypes are possible for the naltrexone-oprm1 drug-gene pair Normal OPRM1 Expresser Reduced OPRM1 Expresser Response Response PGT provides information about how genetic differences in a patient s OPRM1 gene may impact their response to naltrexone therapy Typical response to naltrexone More likely to respond to naltrexone for treatment of alcoholism 2015 Millennium Health, LLC 39 Crist RC, Berrettini WH. Pharmacogenetics of OPRM1. Pharmacol Biochem Behav Aug;123: Millennium Health, LLC 40 Case: Karen PGT Results HTR2C - DRD2 HLA-B15:02 OPRM1 Reduced Expressor Increased abstinence days 1 Lower rates of relapse 2 Karen is prescribed naltrexone 1. Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology Aug;28(8): Anton RF, Oroszi G, O'Malley S, et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. 41 Arch Gen Psychiatry Feb;65(2): Millennium Health, LLC 42 7

8 Patient Reports Patient Bipolar Demonstrate pdfs Wallet Card Summary Test results give clinically actionable info Quality of reports depends on quality of information submitted Does not tell us that a medicine will or will not work. Helps tailor personalized medicine More rapidly treat depression / addiction

9 49 50 Roy E. Smith, MD Addiction Medicine Pavillon 241 Pavillon Place Mill Spring, NC (800)