2Ethnic Variability in Drug Response How do we prescribe drugs?How do we individualize therapy?
3Oops! Toxicity No Effect Too Much Too Little ¯ Dose Dose No effect
4Ethnic Variability and Bridging Studies We recognize that:One dose does not fit allBut - What to do?
5In the Age of the Genome Why Do People Respond Differently to Drugs? Variability in:-Drug metabolism genotypeDrug transporter genotypeDrug receptor genotypeDrug/drug/environment /genotype interactions
6Drug Oxidation - Major Route of Drug Metabolism Family of enzymes (CYPs) in liverProportion of Pharmaceuticals Metabolized by Individual Cytochrome P450’sMajor P450 Content of Human LiverShimada et al, 1994
7Polymorphism of Drug Oxidation CYP2D6 Debrisoquin/SparteineCYP2C19 MephenytoinCYP2C9 S-warfarin
8Frequency of the Defective CYP2C9 Alleles in Different Ethnic Groups PopulationCYP2C9*2CYP2C9*3CYP2C9*4CYP2C9*5Caucasian-AmericanHispanic-AmericanAfrican-AmericanChineseJapanese12.3%12.0%2.5%*0%*5.6%3.4%1.8%4.1%0%0%0%0.5%1.6%* P < 0.001
24H. pylori Cure Rate Based on CYP2C19 Genotype Total cure rate = 52% (n=62)Percent cure ratewt/wt(n=28)wt/m1wt/m2(n=25)m1/m2m1/m1(n=9)Omeprazole 20 mg/day for 6-8 weeksAmoxicillin 2000 mg/day for 2 weeksT. Furuta et al., Ann. Int. Med., 129: , 1998
25Bridging Studies - Ethnicity RealityPopulation differences due toGeneticsEnvironment
26Genetic Polymorphism Two Populations EMs Clearance 100L/minPMs Clearance 1L/min
27Ethnic Differences in Drug Clearance FrequencyPopulation A80%20%FrequencyPopulation B98%2%Cl100L/min1L/minExtensiveMetabolizerPoorMetabolizerMean Clearance80.2 L/min98L/min
29Individual Doses Will Be No More Appropriate In FactEMs and PMs should receive different doses (by a factor of 100 fold)18% reduction in average dose—not appropriate to either populationDoes not improve safety
30Goal of Bridging Studies To adjust dose to different populationsAssumption is that such dosage adjustment is generalizable to entire population
31Ethnicity in Drug Development Define genotypeDispositionResponseEthnic differences in genotype distribution?YesEthnic difference will bepredictedFurther studies needed?NoEthnic difference suggested?NoStopYesEnvironmentalfactorsRequire genotype/phenotype matchingUnrecognizedgenotypeRequire genotype/phenotype matchingYesNoStop
32Genotypes, Variability and Bridging Studies Science has advancedEthnic genotypic variability definedOpportunity to rethink strategyNeed to develop new paradigm