Ethnic Variability in Drug Response How do we prescribe drugs? How do we individualize therapy?

Oops! Toxicity No Effect Too Much Too Little ¯ Dose ­ Dose No effect

Ethnic Variability and Bridging Studies We recognize that: One dose does not fit all But - What to do?

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

Drug Oxidation - Major Route of Drug Metabolism Family of enzymes (CYPs) in liver Proportion of Pharmaceuticals Metabolized by Individual Cytochrome P450’s Major P450 Content of Human Liver Shimada et al, 1994

Polymorphism of Drug Oxidation CYP2D6 Debrisoquin/Sparteine CYP2C19 Mephenytoin CYP2C9 S-warfarin

Frequency of the Defective CYP2C9 Alleles in Different Ethnic Groups Population CYP2C9*2 CYP2C9*3 CYP2C9*4 CYP2C9*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% 0% 0.5% 1.6% * P < 0.001

CYP2C9 Substrates tolbutamide phenytoin S-warfarin glipizide tamoxifen diclofenac ibuprofen piroxicam suprofen S-naproxen sulfamethoxazole torsemide losartan busipirone

CYP2C9 and Glipizide Kidd et al., Pharmacogenetics, 9: 71-80, 1999.

Warfarin Racemic mixture of (R) and (S) isomers (S)warfarin à 7-hydroxywarfarin by CYP2C9 (R)warfarin à 8-hydroxywarfarin by CYP2C19 (S) 7-10 X potency of (R) as anticoagulant

CYP2C9 Reduced (S)-Warfarin Clearance in Heterozygotes Takahashi, CPT, 1998

Warfarin Response in AC Clinic Low dose < 1.5 mg/day Random AC Clinic > 1.5 mg/day Lancet 353: 717; 1999

Warfarin Dose and Genotype CYP2C9 *1/*1 *1/*2 *1/*3 *2/*3 *2/*2 *3/*3 < 1.5 mg/day 19% 33% 28% 14% 6% 0% > 1.5 mg/day 62% 17% 19% 0% 2% Community 60% 20% 17% 2% 0% 1% Lancet 353: 717; 1999

< 1.5 mg/day > 1.5 mg/day INR > 4 at Induction Minor bleeds (per person years) Major bleeds 56% 5.3% 8.3% 17% 1.9% 2.3% Lancet 353: 717; 1999

Genetic Causes of Abnormal Metabolism Within a Phenotype Abnormal alleles Gene duplication

CYP2D6 - Effects of Gene Duplication Dalen et al., 1998.

Genetic Polymorphism CYP2C19 Index drug: Mephenytoin (R and S) S-hydroxylation of mephenytoin deficient in PM’s

Frequency of CYP2C19 Poor Metabolizers Phenotype Genotype Africans African-Americans Caucasians Chinese Japanese Koreans Amerindians 4.1 1.4 2.8 13.6 20.3 13.7 3.8 3.3 2.1 13.8 17.0 16.8 5.7 14

Frequency of CYP2C19 Poor Metabolizers % Phenotype Genotype Blacks Caucasians Chinese Japanese* Koreans* 3.9 2.8 13.6 20.3 13.7 3.7 2.1 13.8 17.0 16.8 Annual Review of Pharmacology & Toxicology 41:815-850, 2001 * British Journal of Pharmacology 48:402-408, 1999 14

CYP2C19 Substrates S-mephenytoin hexobarbital R-mephobarbital diazepam citalopram omeprazole lansoprazole pantoprazole R-warfarin (8-OH) propranolol (in part) imipramine clomipramine amitryptylline proguanil teniposide nilutamide indomethacin moclobemide

CYP2C19 l PMs ¡ EMs Time after Omeprazole (hour) Sohn, JPET 262: 1195-1202; 1992

CYP2C19 Genotype + Intragastric pH Placebo Omeprazole Furuta et al., Clin Pharmacol Ther 65: 552-561, 1999.

H. pylori Cure Rate Based on CYP2C19 Genotype Total cure rate = 52% (n=62) Percent cure rate wt/wt (n=28) wt/m1 wt/m2 (n=25) m1/m2 m1/m1 (n=9) Omeprazole 20 mg/day for 6-8 weeks Amoxicillin 2000 mg/day for 2 weeks T. Furuta et al., Ann. Int. Med., 129: 1027-1030, 1998

Bridging Studies - Ethnicity Reality Population differences due to Genetics Environment

Genetic Polymorphism Two Populations EMs Clearance 100L/min PMs Clearance 1L/min

Ethnic Differences in Drug Clearance Frequency Population A 80% 20% Frequency Population B 98% 2% Cl 100L/min 1L/min Extensive Metabolizer Poor Metabolizer Mean Clearance 80.2 L/min 98L/min

Dose A 18% < B Rational?

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 dose—not appropriate to either population Does not improve safety

Goal of Bridging Studies To adjust dose to different populations Assumption is that such dosage adjustment is generalizable to entire population

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? No Stop Yes Environmental factors Require genotype/ phenotype matching Unrecognized genotype Require genotype/ phenotype matching Yes No Stop

Genotypes, Variability and Bridging Studies Science has advanced Ethnic genotypic variability defined Opportunity to rethink strategy Need to develop new paradigm