Genotype – Guided Warfarin Dosing

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This presentation was given during PharmD study in the Hebrew University in Jerusalem by Orly Shimoni

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  • 1. Genotype Guided Warfarin Dosing Orly Shimoni July 2009

2. , . - 2: 1. , - , , . )CYP450(. 2. - , . . , . 3. - - SNP (Single Nucleotide Polymorphism(- , , " . . - 2 .) 1%.( . - . - 4. - -2 Haplotype- . 5. . " Cytochrome P450. CYP " CYP1 " CYP1A CYP 2E1. , " 1. * 6. Cytochrome P450 57 . phase1 , ) .( CYP1, CYP2, CYP3 . 7. CYP2C9 . - 15% . - 29 CYP2C9*3-CYP2C9*2 S- WARFARIN. . 8. Background - Warfarin Mechanism: Inhibits regeneration of vitamin K(1) epoxide, inhibiting synthesis of vitamin K- dependent clotting factors in liver Peak response: Full anticoagulant effect in 72-96 hours 9. Background - Warfarin Monitoring: International Normalized Ratio (INR) Measurement of extrinsic pathway activity Goal INR 2-3 (sometimes 2.5-3.5) Low INR: increased clotting risk High INR: increased bleeding risk Indications: Atrial fibrillation, deep vein thrombosis, pulmonary embolism, cerebrovascular accident, many others 10. Background - Warfarin Dosing: Algorithms vary widely Common dose/day= 5mg Dose Variations: 20mg daily Dose related side effects: Nose bleeds to death 11. Background - Warfarin R-warfarin metabolism CYP1A2 to 6- and 8- hydroxywarfarin CYP3A4 to 10-hydroxywarfarin Carbonyl reductases to alcohols S-warfarin metabolism CYP2C9 to 6- and 7- hydroxywarfarin Relative potencies: S-isomer ~3 times more potent that R-isomer 12. Background Warfarin Interactions Drug-drug interactions Enzyme inhibition / induction: CYP2C9 CYP3A4 CYP1A2 Alteration of intestinal flora Drug-diet interactions: Vitamin K Alcohol Smoking Warfarin is the most widely used oral anticoagulantWarfarin is the most widely used oral anticoagulant agent worldwide; more than 30 million prescriptionsagent worldwide; more than 30 million prescriptions were written for this drug in the United States in 2004were written for this drug in the United States in 2004 13. Select drug class interactions 5-lipoxygenase Inhibitors Antiparasitic/Antimicrobials HMG-CoA Reductase Inhibitors Adrenergic Stimulants, Central Antiplatelet Drugs/Effects Leukotriene Receptor Antagonist Alcohol Abuse Reduction Agents Antithyroid Drugs Monoamine Oxidase Inhibitors Analgesics Beta-Adrenergic Blockers Narcotics, prolonged Anesthetics, Inhalation Cholelitholytic Agents NSAIDS Antiandrogen Diabetes Agents, Oral Proton Pump Inhibitors Antiarrhythmics Diuretics Psychostimulants Antibiotics Fungal Medications Pyrazolones Aminoglycosides (oral( Gastric Acidity and Peptic Ulcer Agents Salicylates Cephalosporins, parenteral Gastrointestinal Prokinetic Agents SSRIs Macrolides Ulcerative Colitis Agents Steroids, Adrenocortical Penicillins Gout Treatment Agents Steroids, Anabolic Fluoroquinolones Hemorrheologic Agents Thrombolytics Sulfonamides, long acting Hepatotoxic Drugs Thyroid Drugs Tetracyclines Hyperglycemic Agents Tuberculosis Agents Anticoagulants Hypertensive Emergency Agents Uricosuric Agents Anticonvulsants Hypnotics Vaccines Antidepressants Hypolipidemics Vitamins Antimalarial Agents Bile Acid-Binding Resins Antineoplastics Fibric Acid Derivatives 14. Standard Dosing Algorithm Standard Dosing: Days 1,2: 10mg daily; 5mg thereafter or per INR INR measured days 0, 3, 5, 8, 21, 60, 90, and as clinically indicated Adjusted dose given beginning Day 3 based on algorithm 15. Standard Dosing Algorithm INR 1.0-1.59 -Inquire about s/sx of clotting, refer to appropriate care, give extra dose (average day 5-7 dose for day 8) -Increase weekly dose by 10% -INR in 5 days, 14 days INR 1.6-1.79 -Extra half dose today (average of days 5-7 for day 8) -Increase weekly dose by 5% -INR in 7 days, 14 days INR 1.8-1.99 1st Time: -INR in 14 days Repeat: -Increase weekly dose by 5%; INR in 14 days INR 2.0-3.0 -INR in 14 days after day 8, then monthly INR 3.01-3.39 1st Time: -INR in 14 days Repeat: -Decrease weekly dose by 5%; INR in 14 days INR 3.4-4.99 -Reduce todays dose by a half if INR =4. -Decrease weekly dose by 10% -INR in 7 days, 14 days INR > 5.0 -Inquire about s/s bleeding, refer to an appropriate facility for care. Omit 2 doses -INR in 48 hours -When retested INR falls into 1.8-3.39 range, decrease weekly dose by 15%; INR in 7 days, 14 days -If INR>9, follow special protocol 16. Standard Dosing Algorithm 17. CYP2C9 SNPs ) ) VKORC1 SNPs .)) - VKOR3673, haplotype A, haplotype*2 . 18. Genetics and warfarin response CYP2C9: Two SNPs impair metabolism of S-warfarin: *2 and *3 alleles are associated with increased bleeding and decreased warfarin requirement *2 and *3 variants are found in 11% and 8% of whites and 3% and 0.8% of blacks Patients who are homozygous for the wild type allele (CYP2C9*1), S-warfarin is cleared normally, resulting in a modest elevation of the INR. 19. CYP2C9 SNPs CYP2C9*2 is the SNP in exon 3 (CGT>TGT) CYP2C9*3 is in exon 7 (ATT>CTT) Patients with one or two of these SNPs have reduced warfarin requirements and a 2-to 3-fold elevated risk of an adverse event when beginning warfarin. 20. CYP2C9 Genotype & Warfarin Dose 21. Genetics and warfarin response Vitamin K Epoxide Reductase Group 1 (VKORC1): Location: Chromosome 16 (16p11) Prior study of intron 1 SNP rs9934438 (C1173T): Warfarin requirement higher (6.2mg) among CC patients than in CT (4.8 mg) or TT (3.5 mg). Approximate population frequencies CC 37%, CT 50%, TT 13% More recently, 10 common SNPs, all noncoding, divide into 5 haplotypes which form two distinct evolutionary groups. 22. Genetics and warfarin response 2 Major VKORC1 haplotypes: Designated A (low dose) and B (high dose): A/A: 2.7mg/day A/B: 4.9mg/day B/B: 6.2mg/day Haplotype data as informative as single SNPs 23. VKORC1 and CYP2C9 24. Genetics and warfarin response FDA, August 16, 2007: Package insert for warfarin changed to include information on CYP2C9 and VKORC1 genotyping and their role in determining drug clearance and steady-state dose requirements lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes as well as for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR responses to COUMADIN 25. Incidence of CYP2C9 and VKORC1 SNPs(%) Caucasian African- American Other Asian CYP2C9 *2 13.1 5.2 10.4 0 CYP2C9 *3 6 1 4.2 4 VKORC1 Group A 36.6 9.5 41.7 85 VKORC1 Group B 63.4 90.5 58.3 14 26. Advantages of PG Majority of the variance can be predicted using genes and several clinical factors personalized medicine Genetic platforms available Fewer surprises Faster to stable INR Less AEs More time in range over first 30 days Patient acceptance high Web or computer based dosing guidance available 27. Barriers to PG Not many multi-centered RCT Unknown benefit in some patient populations Cost Availability Clinician knowledge Potential delay in medication initiation 28. CYP2C9 Genotype-Guided Warfarin prescribing enhances the efficacy and safety of Anticoagulation A Prospective Randomized Controlled Study Patients were randomly assigned to receive Warfarin by a validated algorithm (control, 96 patients) or CYP2C9 genotype-adjusted algorithms (study 95 patients). 29. Flow of patients through the study 30. Patients demographic details and baseline clinical characteristics 31. Pharmacodynamic end points In the study group first therapeutic INR was reached 2.73 days earlier than in the control group. Warfarin cumulative dose until first therapeutic INR was achived was 41.7% higher in the control group, but it was given over a longer period of time, average Warfarin daily dose was 22% lower in the study group. 32. Anticoagulation details during initiation phase 33. Pharmacodynamic end points The use of higher daily dose in the study group was not associated with higher rate of over anticoagulation (INR>3). The percent time spent within the therapeutic range was 1.85-fold higher in the study group. Among patients in the control group, time to first therapeutic INR, total Warfarin dose, and average daily Warfarin dose did not vary across the 3 major genotypic groups. Among patients in the study group as expected from the study design, Warfarin cumulative dose and average daily dose up to therapeutic INR were dependent on CYP2C9 genotype (p=0.01, and