PERSONALIZED MEDICINE

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1 Clinical Applications of Pharmacogenomics- Based Medicine in Pediatrics Michael D. Reed, PharmD, FCCP, FCP Director, Rebecca D. Considine Research Institute Division of Clinical Pharmacology & Toxicology Associate Chair, Department of Pediatrics Children s Hospital Medical Center of Akron and Professor of Pediatrics Northeast Ohio Medical University U.S. News and World Report, 14 January 2003

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3 Interindividual Variability in Drug Response Disease Asthma Hypertension Solid Cancers Depression Diabetes Arthritis Schizophrenia Drug Class Rate of Poor Response Beta-agonists agonists % Various 30% Various 70% SSRIs, tricyclics 20-40% Sulfonylureas, others 50% NSAIDs, COX-2 inhibitors 30-60% Various 25-75% Factors Contributing to Interindividual Variability in Drug Disposition and Action Age Race/ethnicity it Weight Gender Concomitant Diseases Concomitant Drugs Social factors GENETICS PERSONALIZED MEDICINE

4 The Four DNA Bases Slide 8 Adenosine Cytosine Thymine Guanine

5 The Human Genome Every genome is different: ~ 3 billion basepairs (100%) ~ 100 new variations per individual ~ 3 million genetic variations (0.1%) Genetic variations can be used to explain inter- individual differences in drug response. Age and disease can be used to explain intraindividual differences in drug response The Genome and Drugs Genes encode proteins or enzymes. Differences in the sequence of a gene can cause differences in enzymes. This is why enzymes appear in different forms in individuals. This is also why different people p process one and the same drug differently.

6 The Foundation of Pharmacogenomics: Differences in the Genetic Code Between People Mutation: difference in the DNA code that occurs in less than 1% of population Often associated with rare diseases» Cystic fibrosis, sickle cell anemia, Huntington s disease Polymorphism: difference in the DNA code that occurs in more than 1% of the population p A single polymorphism is less likely to be the main cause of a disease Polymorphisms often have no visible clinical impact Genetics vs. Genomics: TomAto or TomOto Pharmacogenetics Association between a single gene and drug response variability» Gene + Medication Response Pharmacogenomics The contribution of multiple genes to drug response variability» Gene1+Gene2+Gene3+ GeneX + Medication Response

7 Current Concept of Pharmacogenomics Roden DM et al. Ann Intern Med 2006; 145: SNP Variability in The Human Genome 2.85 billion base pairs ~22,000 genes 1.7% of the genome codes for protein 3.3% of the genome is as conserved as the 1.7% that codes for protein On average 1 SNP/1.2kb million SNPS that occur at > 1% frequency ~450,000 SNPS in Multiply Conserved Regions Copy number variations exist in 5-7.5% of the germline genome Most tumor DNA sequence is identical to that of the host 4-5% of the genome is in areas with high copy number variation

8 Clinical Relevance Can we predict who will derive an optimal response? Can we predict who will have a toxicity? Host (patient) genotype determines optimal drug therapy approach Disease (pathogen) genotype determines optimal drug therapy approach Pharmacogenomics DRUG TARGETS DRUG TRANSPORTERS DRUG METABOLIZING ENZYMES PHARMACODYNAMICS PHARMACOKINETICS Variability in Efficacy/Toxicity Johnson JA. Trends in Genetics 2003:

9 Fourteen Drugs and Their Available Pharmacogenetic Tests 2014 Abacavir Clopidogrel Tamoxifen metformin Imatinib 5-Fluorouracil Clozapine QT-prolonging Drugs Irinotecan Azathioprine and Mercaptopurine Warfarin Carbamazepine Interferon HLA *B5701 CYP2C19 CYP2D6 OATP3 BCR-ABL DPYD-TYMS 2 SNPs in HLA-DQB1 Familion TM UGT1A1 TPMT CYP2C9 and VKOR HLA-B* 1502 IL 28B Examples of Drug Metabolism Pharmacogenomics New Engl J Med 2003; 348:

10 Examples of Drug Metabolism Pharmacogenomics New Engl J Med 2003;348: Clinically Important Drug-Drug Interactions: The Importance of Hepatic Cytochrome 450 Isozyme Activity Cytochrome Isozyme Poly- morphism Substrate Inhibitors Inducers 1A2 2C9 2C19 Yes Yes 3-5% Cauc PM 15-20% Asian PM Caffeine, clozapine, cyclobenzaprine, estradiol, fluvoxamine, haloperidol, phenacetin, propranolol, R- warfarin, tacrine, TCA demethylation (amitrip, clomip, imip), theopylline, zileuton Celecoxib, diclofenac, fluoxetine, fluvastatin, irbesartan, ibuprofen, losartan, naproxen, phenytoin, piroxicam, S-warfarin, sulfamethexazole, tolbutamide, tamoxifen Citalopram, cyclophosphamide, diazepam, imipramine, naproxen, propranolol, proton pump Is, phenytoin, R-warfarin, S- mephenytoin, tolbutamide Amiodarone Cimetidine Fluvoxamine Mexiletine Quinolones Ticlopidine Azoles Chloramphenicol INH SSRI s Statins Sulfaphenazole Cimetidine Fluoxetine Fluoxamine Ketoconazole Paroxetine PPI s Ticlopidine Charcoal grill Cigarette smoke Cruciferous vegetables Omeprazole Rifampin Rifampin Carbamazepine (?) Prednisone Rifampin (?)

11 Clinically Important Drug-Drug Interactions: The Importance of Hepatic Cytochrome 450 Isozyme Activity, Continued Cytochrome Isozyme Poly- morphism Substrate Inhibitors Inducers 2D6 Yes Amphetaprine, beta blockers, Celecoxib Rifampin (?) 5-10% captopril, chlorpromazine, codeine, Cimetidine debrisoquine, d-methorphan, Fluoxetine/ Cauc PM ecanide, flecanide, fluoxetine, Norfluoxetine fluvoxamine, imipramine, metaprolol, mexiletine, norfluoxetine, nortriptyline, Paroxetine Quinidine Sertraline ondansetron, paroxetine, propranolol, respiridone, tamoxifen, TCA s (part), thioridazine, timolol, tramadol, venlafaxine 2E1 No Acetaminophen, dapsone, theophylline (?) Ethanol INH Rifampin Clinically Important Drug-Drug Interactions: The Importance of Hepatic Cytochrome 450 Isozyme Activity, Continued Cytochrome Isozyme Poly- morphism Substrate Inhibitors Inducers 3A3/3A4 Possible Alfentanyl, alprazolam, Azoles amlodepine, astemizole, Ciprofloxacin atorvastatin, buspirone, Fluoxetine chlorpheniramine, cisapride, Fluvoxamine clarithromycin, cocaine, Macrolides cyclosporine, diazepam, diltiazem, Naringenin erythromycin, estradiol, fentanyl, Nefazadone haloperidol (part), hydrocortisone, Protease itraconazole, lidocaine, loratadine, inhibitors lovastatin, midazolam, nifedipine, Sertraline omeprazole, ondansetron (part), TAO progesterone, quinidine, (R)(S) warfarin,simvastatin, statins (not pravastatin), tacrolimus, tamoxifen, taxol, TCA demethylation, terfenadine, trazodone, triazolam, verapamil Barbiturates Carbamazepine Glucocorticoids Phenobarbital Phenylbutazone Phenytoin Rifampin

12 CYP2D6 Polymorphisms CYP2D6 is responsible for the metabolism of a number of different drugs Antidepressants, antipsychotics, analgesics, cardiovascular drugs Over 100 polymorphisms in CYP2D6 have been identified Based on these polymorphisms, patients are phenotypically classified as: Ultrarapid metabolizers (UMs) Extensive metabolizers (EMs) Poor metabolizers (PMs) CYP2D6 Phenotypes NEJM 2003; 348:529 Roden DM et al. Ann Intern Med 2006; 145:749-57

13 Incidence of CYP2D6 UM Genotype American 4.3% Turkish African American Ethiopian Saudi Arabian 8.7% 4.9% 29% 21% Columbian 1.7% Bernard et al. Oncologist 2006;11: CYP2D6 Polymorphisms and Psychiatric Drug Response Increased rate of adverse effects in poor metabolizers ers due to increased plasma concentrations of drug: Fluoxetine (Prozac ) death in child attributed to CYP2D6 poor metabolizer genotype Side effects of antipsychotic drugs occur more frequently in CYP2D6 poor metabolizers CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, increased cost of care, and longer hospital stays

14 Strattera (Atomoxetine) Treatment of attention deficit hyperactivity disorder CYP2D6 poor metabolizers have 10-fold higher plasma concentrations to a given dose of STRATTERA compared with extensive metabolizers Approximately 7% of Caucasians are poor metabolizers Higher blood levels in poor metabolizers may lead to a higher rate of some adverse effects of STRATTERA Metabolic Disposition of Selected Opioid Analgesics Opioid Agent Metabolic Disposition Codeine CYP2D6, CYP3A4, UGT2B7 Dihydrocodeine CYP2D6, CYP3A4, UGT2B7 Fentanyl CYP3A4 Hydrocodone CYP2D6, 3A4,UGT, other CYPs Hydromorphone UGT1A3 & 2B7,DyHydroReduc Methadone CYP3A4, CYP2B6 Morphine UGT1A3, UGT2B7 Nalexone UGT2B7 and other UGTs Oxymorphone UGT2B7, UGT1A3 Tramadol CYP2D6, CYP2B6, CYP3A4

15 CYP2D6 and Codeine Codeine requires activation by CYP2D6 in order to exert tit its analgesic effect Due to genetic polymorphisms, 2-10% of the population cannot metabolize codeine and are resistant to the analgesic effects Interindividual variability exists in the adequacy of pain relief when uniform doses of codeine are given Pharmacogenomics and the Breast-Fed Infant Full-term health male infant Vaginal delivery D7: intermittent periods of difficulty in BF and lethargy D11: pediatric office visits; regained birth weight D12: grey skin, milk intake fallen D13: the baby was found dead Unremarkable autopsy: infant morphine 70mg/ml (0-2.2 typical) Mother APAP 500 ml/codeine 30mg pp episiotomy pain 2 tabs q 12h decreased 1 tab q12 day 2 for somnolence and constipation Continued tablets for 2 weeks D10: maternal milk (stored) morphine 87mg/ml (typical mg/ml Maternal CYP2D6*2x2 duplication: UM Explanation Mother ultra rapid metabolizer phenotype Infant with physiologically impaired CYP capacity Question of concurrent unrecognized infant pathology Koren G, et al, Lancet 2006;368(#9536):704

16 Int J Clin Pharm 2011;33:33-43 Examples of Drug Metabolism Pharmacogenomics New Engl J Med 2003;348:529-37

17 Warfarin and CYP2C9 Widely prescribed anticoagulant drug used to prevent blood clots Narrow range between efficacy and toxicity Large variability in the dose required to achieve therapeutic anticoagulation Doses vary 10-fold between people CYP2C9 is the enzyme responsible for the metabolism tbli of warfarin SNPs exist in CYP2C9 gene that decrease the activity of the CYP2C9 metabolizing enzyme CYP2C9 Pharmacogenetics Scordo et al., Clin Pharmacol Ther 72:702-10,2002

18 VKOR and Warfarin Warfarin works by inhibiting Vitamin K Epoxide Reductase (VKOR) VKOR helps recycle vitamin K which is important in proper functioning of clotting factors By inhibiting VKOR, warfarin alters the vitamin K cycle and results in the production of inactive clotting factors Polymorphisms exist in the gene for VKOR (VKORC1) N Engl J Med 2011;264:

19 Warfarin Pharmacogenomics CYP2C9 SNPs account for a small amount of variability in warfarin doses (~10%) VKORC1 SNPs explain a larger portion of variability in warfarin doses (~20-25%) 25%) Almost 50% of variability in warfarin doses can be explained by a combination of factors: VKORC1 SNPs CYP2C9 SNPs Non-genetic factors (age, weight, concomitant drugs, concomitant disease states) Personalized Medicine: Major Obstacle #1 "In a setback for the fledgling field of personalized medicine, Medicare has decided not to pay pyfor genetic tests intended to help doctors determine the best dose of the blood thinner warfarin for a particular patient." The Centers for Medicare and Medicaid Services (CMS), "in a proposed decision posted on its website...said that there was not enough evidence that use of the tests improved patients' health." CMS, however, "said it would pay for the tests as part of clinical trials to gather such evidence." While some research has suggested "that using the genetic test might allow the proper dose to be achieved more quickly," CMS "said there was little evidence that t doing so translated t into a lower risk of blood clots or hemorrhages." The Times adds that "the Food and Drug Administration recommends, but does not require, a genetic test for patients starting on warfarin." May 5, 2009 The New York Times (B3, Pollack)

20 CYP2C19 Pharmacogenetics 1984: Unusual sedation in a subject receiving anticonvulsant mephenytion Impaired 4-hydroxylation of S-mephenytoin Affects 2-5% of Caucasians; 20-25% 25% of Asians Affected drugs include omeprazole, lansoprazole, pantoprazole, diazepam Major clinical consequence at present related to omeprazole pharmacodynamics and efficacy CYP2C19 Genotype Frequencies Morrison A, Levy R. Pharmacogenomics 2004;5:

21 Furuta T, et al: Drug Metab Pharmacokin 20:153,2005 Furuta T, et al: Clin Pharm Ther 65:552,1999

22 Clopidogril and CYP2C19 Clopidogril for Cardiovascular Disease Inhibits ADP-stimulated platelet activation Irreversibly binds to platelet-specific ADP receptor P2Y12 Prodrug: CYP2C19 to active thiol metabolite March 2010: FDA black box warning Soon after AHA & ACC issued joint endorsement of CYP2C19 genotyping Current Standard: dual Rx clopidogril + ASA Despite Pronouncements, Enthusiasm Muted Two large randomized genotype studies = no benefit Lancet 2010;376:1320 (n = 10,285) NEJM 2010;363:1704 (n = 5059) No significant effect on cardiovascular events ACS or AF Drug Abacavir Associations Between Allelic Variants and HIV Treatment Response Indinavir Atazanavir Phenotype Hypersensitivity Gene HLA-B*5701 Lancet 2002:359,727 & 1121; PNAS 2004:101,4180 Jaundice UGT-1A1 PNAS 2001:98,12671; ICAAC 2002; JID 2005;192,1381 NRTI Lipoatrophy TNF-α promoter, HFE AIDS 2002:16,2013; AIDS 2003:17,121; JID 2008:197, 858 Nevirapine Hypersensitivity Hepatotoxicity Pharmacokinetics HLA-DRB1*0101, -Cw8, -B3505 ABCB1 CYP2B6 AIDS 2005:19,97; Pharmacogenet Genom 2005;15,1; Clin Inf Dis 2006;43,779 & 783; AIDS 2006:20,1621; AIDS 2007;21,264; Pharmacogenet Genom 2009;19,139

23 Thiopurine metabolism. Oral AZA is rapidly converted to 6-MP by a nonenzymatic process. Intiial 6-MP transformations occur along competing catabolic (XO, xanthine oxidase; TPMT) and anabolic (HPRT, hypoxanthine phosphoribosyltransferase) enzymatic pathways. Once formed, 6-thiosine 5 -monophosphate (6- TImP) is further catalyzed by inosine monophosphate dehydrogenase (IMPDH), and guanosine monophosphate synthetase (GMPS) and the di- and tri-derivatives of 6-thioguanosine 5 monophosphate (6- TGMP) formed by their respective kinases. T-TU, 6-thiouric acid. Dubinsky MC. Clin Gastro Hepatol 2:731, Suggested Azathioprine Treatment Doses Based Upon Erythrocyte TPMT Activity TMT Activity ty ~ % of Population o Azathioprine Dose (mg) Deficient (very low / absent) 0.3 No Rx or by 90% Intermediate 11 Dose by 15-50% Normal or High 89 Standard Rx Konstantopoulou M, et al; BMJ 330:350, 2005

24 Hematologic Parameters in Adults with Crohn s Disease on Azathioprine REMISSION Parameter Yes (n=14) No (n=31) p Value WBC 5,350 (2,106) 8,918 (3,858) Lymphocytes (%) (6.8) 96(58) 9.6 (5.8) Granulocytes (%) 73 (8.7) 81 (6.9) Data presented as mean (+ SD) Hematologic Parameters in Adults with Ulcerative Colitis on Azathioprine REMISSION Parameter Yes (n=13) No (n=27) p Value WBC 6,045 (1,165) 8,767 (2,356) Lymphocytes (%) 20 (5.3) 12 (5.6) Granulocytes (%) 69 (6.1) 79 (8.9) Data presented as mean (+ SD) Glass J, et al. Eur J Med Res 10:535, Examples of Human Receptors Shown to be Genetically Polymorphic with Possible Alterations in Clinical Phenotype G-proteins ti Angiotensin II receptor and angiotensinogen Angiotensin converting enzyme Β-receptor Dopamine D 4 receptor Endothelial NO synthase 5HT 4 receptor

25 Beta-blockers and Hypertension (HTN) HTN is the most prevalent chronic disease in the US and a contributor to morbidity and mortality Beta-blockers are first-line agent in the treatment of HTN Marked variability in response to beta-blockers blockers 30-60% of patients fail to achieve adequate blood pressure lowering with beta-blockersblockers Common beta-blockers blockers used in HTN: Metoprolol Atenolol Beta-1 Receptor Polymorphisms and Response to Metoprolol Johnson JA et al. Clin Pharmacol Ther 2003; 74:44-52

26 Beta-2 Polymorphisms and Response to Albuterol Single 8 mg albuterol dose Albuterol-evoked l kdincreases in FEV 1 were higher and more rapid in Arg16 homozyotes compared with Gly carriers Codon 16 polymorphism is a determinant of bronchodilator response to albuterol Lima JJ et al. Clin Pharmacol Ther 1999; 65: Lima JJ. Clin Pharmacol Ther 1999; 65: Carbamazepine-Induced Toxic Effects HLA-A A 3101 Genotype and Hypersensitivity Reactions CBZ-induced minor macpap exanthema in 5-10% Euro pts. MP rash: minor form resolves spontaneously after QC SJS & TEN most severe: overall 10% morality (TEN-30%) FDA estimates 1-6/10,000 Euro pts SJS risk HLA-A A 3101 prevalence 2-5% Euro descent Allele presence defined increased risk from 5-26% vs absence reduced risk from 5-3.8% HLA-B 1502 Genotype & HAN Chinese SJS & TEN never occurs in non-carriers Associat confirmed in Hong Kong, Malaysia, Thailand, India Recent study confirmed in Taiwanese (N Engl J Med 2011;364:126) Overall: screens for 1 identified patient N Engl J Med 2011;364:1134

27 Distribution of the HLA-A*3101Allele Allele across the Spectrum of Clinical Phenotypesofof Case Subjects with Carbamazepine- Induced Hypersensitivity and Control Subjects without Adverse Reactions to Carbamazepine. Subjects were recruited at centers collaborating with the University of Liverpool and Walton Centre for Neurology (UK) or centers affiliated with the EPIGEN consortium. The sample obtained from one patient with acute generalized exanthematous pustulosis (AGEP) was analyzed with the samples for the group of case subjects with the hypersensitivity syndrome. Since there were no observations of the HLA-A*3101 allele in the three case subjects with the hypersensitivity syndrome in the EPIGEN cohort, 0.5 was added to each value in a two-by-two contingency table to estimate an odds ratio. One patient with the Stevens Johnson syndrome and toxic epidermal necrolysis (SJS TEN) was of mixed European and Thai ancestry. Study weighting (indicated by different sizes of squares) refers to the proportion of subjects who were recruited from each study cohort. Diamonds indicate pooled odds ratios. The horizontal lines indicate 95% confidence intervals. The abbreviation df denotes degrees of freedom, and I 2 is the percentage of total variation that is due to heterogeneity rather than chance. N Engl J Med 2011;364:12

28 Lessons from CYP Pharmacogenetics Multiple genetic tests of one gene may be needed to accurately predict phenotype Gene duplication in the germline exists The environment in the form of Drug Interactions Can mimic a genetic change

29 Several Potential Goals for Clinical Pharmacogenetic Testing The sub-division of common diseases into different molecular sub-types which may be more or less susceptible to specific treatments. To evolve more logical approaches to dosage, efficacy and the prevention of adverse reactions by analyzing the genetic basis for differences in the pharmacokinetic or pharmacodynamic properties of drugs. To identify genetic susceptibility to various common diseases that offer targets for pharmacological intervention. Summary Pharmacogenomic testing is now being widely applied to some of the most widely prescribed drugs Pharmacogenomic biomarkers require demonstration of clinical utility before widespread implementation This has happened in very few cases to date Clinical pharmacogenomic predictive tests must provide real value over existing gp predictors Economic utility is often as important as clinical utility

30 Pharmacogenetics Websites The SNP consortium: The Human Genome: CYP alleles: Drug Interactions: REFERENCES 1. Rassekh SR, Ross CJ, Carleton BC, Hayden MR. Cancer pharmacogenomics in children: research initiatives and progress to date. Paediatr Drugs Apr;15(2): doi: /s Review. PubMed PMID: Hawcutt DB, Thompson B, Smyth RL, Pirmohamed M. Paediatric pharmacogenomics: an overview. Arch Dis Child Mar;98(3): doi: /archdischild Epub 2012 Nov 29. Review. PubMed PMID: Wall CA, Croarkin PE, Swintak C, Koplin BA. Psychiatric pharmacogenomics in pediatric psychopharmacology. Child Adolesc Psychiatr Clin N Am Oct;21(4): doi: /j.chc Review. PubMed PMID: Wagner J, Leeder JS. Pediatric pharmacogenomics: a systematic assessment of ontogeny and genetic variation to guide the design of statin studies in children. Pediatr Clin North Am Oct;59(5): doi: /j.pcl Epub 2012 Aug 22. Review. PubMed PMID: Leeder JS, Kearns GL. Interpreting pharmacogenetic data in the developing neonate: the challenge of hitting a moving target. Clin Pharmacol Ther Oct;92(4): doi: /clpt Epub 2012 Sep 5. Review. PubMed PMID: Becker ML. Pharmacogenomics in pediatric rheumatology. Curr Opin Rheumatol Sep;24(5): doi: /BOR.0b013e d13. Review. PubMed PMID: