Genetic Screening for ADR

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1 Genetic Screening for ADR Mahidol University Faculty of Medicine Siriraj Hospital Manop Pithukpakorn, MD Division of Medical Genetics Department of Medicine

2 concentration Drug level over time toxic optimum ineffective time

3 Adverse Drug Reaction Type A (on-target) vs type B (off-target) ADR prevention is important to reduce morbidity/mortality, also to improve compliance. Discontinuation of effective treatment because of ADR is also detrimental Approximately 20 30% of ADR could be prevented by pharmacogenetic testing At least 10% of drug labels in EU/USA contain information on genetic factors determining drug response

4 Pharmacogenetics (-genomics) Genetic variation that gives rise to the variable responses in individuals to any given drug treatment Pharmacokinetics and Pharmacodynamics Efficacy of treatment (Choice of treatment) Adverse effect of medications (Determine dosing/avoid using) Personalized therapy based on an individual s genotype

5 Conventional Treatment

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7 Use of genetic test for ADR Diagnose Understand Predict Genetic test Pre-empt Exclude Monitor

8 Genetics of ADR

9 Drug metabolism phenotypes Poor metabolizer: homozygous null Intermediate metabolizer: heterozygous null, hypomorphic Rapid metabolizer: wild-type Ultra-rapid metabolizer: copy number variants/duplication

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11 CYP2D6 allele frequency Tan SH. et al, Clin Cancer Res 2008

12 Cytochrome P450

13 Cytochrome P450

14 Warfarin Metabolism 6-hydroxywarfarin 8-hydroxywarfarin CYP2C19 CYP1A1 CYP1A2 7-hydroxywarfarin CYP2C9 6-hydroxywarfarin CYP3A4 10-hydroxywarfarin 7-hydroxywarfarin R-Warfarin S-Warfarin CYP1A2 CYP2C9 CYP1A1 CYP2C18 CYP2C8 4-hydroxywarfarin CYP2C9 dehydroxywarfarin

15 Warfarin Mechanism of Action R-Warfarin S-Warfarin EPHX1 VKORC1 Hydroxy-Vitamin K CYP4F2 Vitamin K (epoxidized) Vitamin K (reduced) active inactive F10 F2 F2 F10 F7 F9 F9 F7

16 Genotype-guided vs Clinical algorithm COAG vs EU-PACT trial Kimmel SE, et al. N Engl J Med (2013) Pirmohamed M, et al. N Engl J Med (2013)

17 Genotype-guided warfarin dosing FDA Warfain Label

18 Genotype-guided warfarin dosing Fixed & Clinical algorithm Genotype-guided algorithm Ravvaz K, et al. Circ Cardiovasc Genet (2017)

19 Genotype-guided warfarin dosing

20 Azathioprine/6-MP Metabolism AZA 6-MP XO Me-MP TMPT HGPRT Thiourate Me-TIMP TMPT 6-TIMP IMPDH 6-TXMP Me-TGMP TMPT 6-TGMP

21 TPMT Activity and Dosage TPMT polymorphisms *3A, *3B, *3C and *2 result in significant decreases in enzyme activity TPMT*3A (5% in Caucasian) TPMT*3C (2% in East Asian/African) Evans WE. Ther Drug Monit (2004)

22 Irinotecan Metabolism (TA) 6 variant UGT1A1 SN-38 glucuronides Irinotecan (prodrug) SN-38 UGT = uridine glucuronosyltransferase

23 Irinotecan Metabolism (TA) 7 variant UGT1A1*28 SN-38 glucuronides Irinotecan (prodrug) SN-38 UGT = uridine glucuronosyltransferase

24 Cutaneous Adverse Drug Reactions Incidence of cutaneous and/or systemic drug reactions varies for each medication Most are type B reaction (idiosyncratic, doseindependent) Estimated severe cutaneous ADR ~0.2% among users

25 Specific HLA and ADR Drug HLA ADR Allopurinol HLA-B*58:01 SJS, TEN, DRESS Carbamazepine HLA-B*15:02, A*31:01 SJS, TEN, DRESS Abacavir HLA-B*57:01 Hypersensitivity Dapsone HLA-B*13:01 Hypersensitivity Antithyroid Synthetic erythropoietin HLA-B*27:05, B*38:02, DRB1*08:03 HLA-DRB1*09, DQB1*0309 Agranulocytosis Anti-EPO pure red cell aplasia

26 Carbamazepine, Allopurinol, Abacavir Carbamazepine : Antiepileptics used in seizure and neuropathy Allopurinol : Xanthine oxidase inhibitor used in hyperuricemia Abacavir : Antiretroviral nucleoside analog Severe cutaneous ADR, systemic ADR (DRESS)

27 Carbamazepine and SJS Chung W-H, et al. Nature 2004 Apr. 428:486

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29 Rufini S, et al. Pharmacogenomics Nov;16(17):

30 Hung S-L, et al. Proc Natl Acad Sci 2005 Mar. 102(11):

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32 Patients fulfill indications for CBZ/allopurinol treatment New cases Long term use 7-10 business days HLA test B*1502 for CBZ B*5801 for allopurinol Reimbursement G.O. only 1,500 baht/test Test negative for B*1502/B*5801 Test positive for B*1502/B*5801 Documentation Medication initiated Alternative treatment is recommended

33 Pharmacogenetics & ADR of common drugs Drugs Gene/Allele ADR Abacavir HLA-B*57:01 Hypersensitivity Allopurinol HLA-B*58:01 SJS, TEN, DRESS Antithyroid HLA-B*27:05, B*38:02, Agranulocytosis DRB1*08:03 Atazanavir UGT1A1 Jaundice Aza/6-MP/6-TG TPMT Myelosuppression HLA-DRB1*07:01, Azathioprine Pancreatitis DQB1*02:01 Capecitabine, 5-FU DPYD Neutropenia, mucositis, neuropathy Carbamazepine HLA-B*15:02 SJS, TEN Clopidogrel CYP2C19 Bleeding, MI/Stroke, Thrombosis Clozapine HLA-B(158T), HLA-DQB1*05:02 Agranulocytosis

34 Pharmacogenetics & ADR of common drugs Drugs Gene/Allele ADR Codeine CYP2D6 Respiratory suppression Doxorubicin RARG, SLC28A3 Cardiotoxicity Estrogen Factor V Leiden Thrombosis Irinotecan UGT1A1 Myelosuppression, GI side effects Phenytoin HLA-B*15:02, CYP2C9 SJS, TEN Rasburicase G-6-PD Hemolysis Simvastatin SLCO1B1 Myositis Tacrolimus CYP3A5 Drug toxicity, nephrotoxicity Warfarin CYP2C9, VKORC1 (CYP4F2) Bleeding

35 PharmGKB

36 PharmGKB

37 Use of genetic test for ADR Suspected ADR cases Diagnose Research Understand Warfarin, Aza/6-MP Predict Genetic test CYP Pre-empt pharmacogenetic panel Monitor Exclude Allopurinol, CBZ RasB, Abac Warfarin, CBZ (31:01), Antithyroid

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