Presentation on theme: "Alastair J.J. Wood. Ethnic Variability in Drug Response How do we prescribe drugs? How do we individualize therapy?"— Presentation transcript:
Alastair J.J. Wood
Ethnic Variability in Drug Response How do we prescribe drugs? How do we individualize therapy?
Alastair J.J. Wood ToxicityNo Effect Oops! Too MuchToo Little Dose No effect Dose Toxicity Dose
Alastair J.J. Wood Ethnic Variability and Bridging Studies We recognize that: One dose does not fit all But - What to do?
Alastair J.J. Wood In the Age of the Genome Why Do People Respond Differently to Drugs? Variability in:- Drug metabolism genotype Drug transporter genotype Drug receptor genotype Drug/drug/environment /genotype interactions
Alastair J.J. Wood Drug Oxidation - Major Route of Drug Metabolism Family of enzymes (CYPs) in liver Proportion of Pharmaceuticals Metabolized by Individual Cytochrome P450s Major P450 Content of Human Liver Shimada et al, 1994
Alastair J.J. Wood Polymorphism of Drug Oxidation CYP2D6Debrisoquin/Sparteine CYP2C19Mephenytoin CYP2C9S-warfarin
Alastair J.J. Wood Frequency of the Defective CYP2C9 Alleles in Different Ethnic Groups Population CYP2C9*2CYP2C9*3CYP2C9*4CYP2C9*5 Caucasian-American Hispanic-American African-American Chinese Japanese 12.3% 12.0% 2.5%* 0%* 5.6% 3.4% 1.8% 4.1% 0% 0.5% 1.6% 0% * P < 0.001
Alastair J.J. Wood Ethnic Differences in Drug Clearance Extensive Metabolizer Poor Metabolizer Mean Clearance Cl 100L/min 1L/min Frequency Population A 80% 20% Frequency Population B 98% 2% 80.2 L/min 98L/min
Alastair J.J. Wood Dose A 18% < B Rational?
Alastair J.J. Wood Individual Doses Will Be No More Appropriate In Fact EMs and PMs should receive different doses (by a factor of 100 fold) 18% reduction in average dosenot appropriate to either population Does not improve safety
Alastair J.J. Wood Goal of Bridging Studies To adjust dose to different populations Assumption is that such dosage adjustment is generalizable to entire population
Alastair J.J. Wood Ethnicity in Drug Development Define genotype Disposition Response Ethnic differences in genotype distribution? Yes Ethnic difference will be predicted Further studies needed? No Ethnic difference suggested? Require genotype/ phenotype matching Yes Unrecognized genotype NoStop NoStop Yes Environmental factors Require genotype/ phenotype matching
Alastair J.J. Wood Genotypes, Variability and Bridging Studies Science has advanced Ethnic genotypic variability defined Opportunity to rethink strategy Need to develop new paradigm