2/28/2010. Pharmacogenomics and the Asian Population. Limited efficacy/response to drugs already on the market

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1 Pharmacogenomics and the Asian Population Majority are medication related Alan H.B. Wu, Ph.D. Professor, Laboratory Medicine, UCSF Section Chief, Clinical Chemistry, February 27, 20 Limited efficacy/response to drugs already on the market ACE inhibitors -30% Beta Blockers 15-35% Statins -60% Alzheimer s: 30 % Analgesics 80 % Asthma: 60 % Cardiac Arrythmias: 60 % Depression (SSRI): 62 % Diabetes: 57 % Hepatitis C: 47 % Incontinence: 40 % Migraine (acute): 52 % Migraine (prophylaxis): 50 % Oncology: 25 % Rheumatoid arthritis: 50 % Schizophrenia: 60 % Emerging area in lab medicine: Personalized medicine 1

2 Translation of PGx into clinical practice Conversion of genotype data directly into clinical management decisions: Cytochrome P Optimizing dosing for maximum efficacy and toxicity avoidance 2. Selecting drugs that avoids side effects. 3. Selecting drugs that have the highest rate of therapeutic efficacy PGx useful No PGx FDA Re-labeling Initiative Who is the driver for PGx? Drug Enzyme Goal Year Status Warfarin Tamoxifen Abacavir Allopurinol Carbamazep Phenytoin Clopidogrel CYP 2D6 VKORC1 CYP 2D6 HLA-B*5701 HLA-B*5801 HLA-B*1502 CYP 2C19 Safety Efficacy Safety Safety Safety Safety Efficacy

3 Warfarin Challenges in warfarin treatment J Gen Intern Med 1998;13:311-6 Warfarin has a complex dose-response relationship making safe and effective use a challenge. More than 7% of out-patients suffer a major hemorrhage* 1/3 of INR values > target therapeutic range in first month* Why relabel warfarin? Warfarin PGx DOSING SCHEDULES (VKORC1) 3

4 Warfarin dosing difficulties Pharmacokinetics + pharmacodynamics Sconce et al. Blood 2005;6: Target INR *2/*3: low dose *1: high dose A: low dose G: high dose Warfarin dosing Using 2C9 & VKORC1 Key to PGx for warfarin: dosing algorithm 4

5 CYP2C9 & VKORC1 polymorphism for warfarin Sconce et al. Blood 2005;6: Ethnic variation for VKORC1: UCSF data Caucasian population H1/H2 A/A Asians H7/H9 G/G Hispanic H7/H9 Whites H7/H9 H3/H6?? African American Regression model using genotype, age, height UCSF warfarin dosing algorithm Wu, Wang et al. Pharmacogen 2008;9: log (Dose) = *(2C9*2) *(2C9*3) *(Age) *(Asian) *(Black) *(Gender) *(Height) *(Hispanic) *(inhibitors) *(other ethnicity) *(smoking) *(VKORC1-1639) *(Weight) *(VKORC1 2255TC) *(VKORC1 2255TT) Validated by University of Louisville 5

6 CYP 2C9 *1/*1 VKORC1 A/A Low warfarin dose phenotype Tamoxifen Metabolism of tamoxifen Jin et al. J Nat Can Inst 2005;97:30-9. CYD 2D6 allele frequencies Bradford et al. Pharmacogen 2002;3: Low concentrations Caucasian Asian African Low SERM potency -0x more potent than tamoxifen 0 Wildtype Null Reduced *1 *4 * 6

7 Tamoxifen therapy and 2D6 * Lim et al. J Clin Oncol 2007;25: Aromatase inhibitor baggage Requires ovarian suppression (chemical menopause with Lupron). Cardiovascular disease Osteoporosis Hypercholesterolemia Vaginal dryness and other symptoms of menopause CYP 2D6 *1/*5 *5 is a gene deletion. Reduced metabolism for tam and other CYP 2D6 substrates. Cardiac drugs: statins and clopidogrel 7

8 Cargo KIF6 Trp719Arg Stalk Microtubule KIF6 encodes a kinesin Tail Two necks Motor domains Death or major CV events Statin intensity and CHD event reduction According to KIF6 719Arg Carrier Status KIF6 Carriers Pravastatin Months of follow-up p Atorvastatin Noncarriers Pravastatin Atorvastatin P= Months of follow-up Kinesins: a family of dimeric motor proteins involved in the intracellular transport of organelles, protein complexes and mrnas Trp719Arg replaces a non-polar residue with a basic residue near the coiled-coil structure and might affect cargo binding or regulation of the motor domain KIF6 carriers received greater benefit from 80 mg atorvastatin, compared with 40 mg pravastatin, than did noncarriers Number Needed to Treat with atorvastatin (vs. pravastatin) for 2 years to prevent 1 event was for KIF6 carriers and 125 for noncarriers Asian noncarrier frequence rate: 40% LDL-C lowering by statin therapy CRP lowering by statin therapy 120 PROVE IT Pravastatin PROVE IT LDL (mg/dl) Atorvastatin Baseline 30 Days 4 Mo 8 Mo 16 Mo Time of Visit KIF6 Carriers Noncarriers CRP (mg/l) 50 Baseline 30 Days 4 Mo Time of Visit KIF6 Carriers Noncarriers Pravastatin Atorvastatin 8

9 Kif-6 carrier Ok for statins Pharmacogenomics of clopidogrel Simon, NEJM 2009;360: Used for the prevention of atherothrombotic events in patients after AMI. More potent than salicylates to block platelet function Pharmacogenomic and pharmacodynamic effects for Plavix Mega et al. NEJM 2009;360: Drug levels-pharmacokinetic effect PGx of clopidogrel Mega et al. NEJM 2009;360: Platelet inhibition--pharmacodynamic effect 9

10 CYD 2C19 allele frequencies Xie et al. Ann Rev Pharmacol Toxicol 2001;41: Percent of population tested Wildtype *2 *3 Caucasian Asian African Am. Eliminating SJS? Percent of surface area of skin: Stevens Johnson Syndrome: <% SJS-TEN overlap: -29% Toxic epidermal necrolysis: 30% Medications implicated: anti-gout agents Antibiotics antipsychotics antiepileptics analgesics NSAIDS Genetic Association between HLA and drug hypersensitivity Human Leukocyte Antigen (HLA) = Human Major Histocompatibility Complex (MHC) HLA Antigen-presenting cell TCR T-cell immune response with memory characteristics CYP 2C19 *1/*2 150 mg plavix? HLA-B*1502 & Carbamazepine: odds ratio 2504 (South-eastern Asians) HLA-B*5801 & Allopurinol: odds ratio 580 (Han Chinese) HLA-B*5701 and Abacavir: odds ratio 960 (Caucasian)

11 one dose of plavix one visit to cardiologist (Fung) $4 $0 A laboratory test that can determine if the clopidogrel is effective in blocking platelet receptors and prolonging survival of your mother with cardiovascular disease? IL PGx Card priceless 11