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Alastair J.J. Wood. Ethnic Variability in Drug Response How do we prescribe drugs? How do we individualize therapy?

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Presentation on theme: "Alastair J.J. Wood. Ethnic Variability in Drug Response How do we prescribe drugs? How do we individualize therapy?"— Presentation transcript:

1 Alastair J.J. Wood

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

3 Alastair J.J. Wood ToxicityNo Effect Oops! Too MuchToo Little Dose No effect Dose Toxicity Dose

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

5 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

6 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

7 Alastair J.J. Wood Polymorphism of Drug Oxidation CYP2D6Debrisoquin/Sparteine CYP2C19Mephenytoin CYP2C9S-warfarin

8 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

9 Alastair J.J. Wood CYP2C9 Substrates tolbutamide phenytoin S-warfarin glipizide tamoxifen diclofenac ibuprofen piroxicam suprofen S-naproxen sulfamethoxazole torsemide losartan busipirone

10 Alastair J.J. Wood CYP2C9 and Glipizide Kidd et al., Pharmacogenetics, 9: 71-80, 1999.

11 Alastair J.J. Wood Warfarin Racemic mixture of (R) and (S) isomers (S)warfarin 7-hydroxywarfarin by CYP2C9 (R)warfarin 8-hydroxywarfarin by CYP2C19 (S) 7-10 X potency of (R) as anticoagulant

12 Alastair J.J. Wood CYP2C9 Reduced (S)-Warfarin Clearance in Heterozygotes Takahashi, CPT, 1998

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

14 Alastair J.J. Wood Warfarin Dose and Genotype Lancet 353: 717; 1999 Genotype (%) CYP2C9*1/*1 *1/*2 *1/*3 *2/*3 *2/*2 *3/*3 < 1.5 mg/day19%33%28%14% 6% 6% 0% 0% > 1.5 mg/day62%17%19% 0% 0% 2% 2% 0% 0% Community60%20%17% 2% 2% 0% 0% 1% 1%

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

16 Alastair J.J. Wood Genetic Causes of Abnormal Metabolism Within a Phenotype Abnormal alleles Gene duplication

17 Alastair J.J. Wood CYP2D6 - Effects of Gene Duplication Dalen et al., 1998.

18 Alastair J.J. Wood Genetic Polymorphism CYP2C19 Index drug: Mephenytoin (R and S) S-hydroxylation of mephenytoin deficient in PMs

19 Alastair J.J. Wood Frequency of CYP2C19 Poor Metabolizers Africans African-Americans Caucasians Chinese Japanese Koreans Amerindians Phenotype Genotype

20 Alastair J.J. Wood Frequency of CYP2C19 Poor Metabolizers % Blacks Caucasians Chinese Japanese* Koreans* PhenotypeGenotype Annual Review of Pharmacology & Toxicology 41: , 2001 * British Journal of Pharmacology 48: , 1999

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

22 Alastair J.J. Wood Time after Omeprazole (hour) CYP2C19 PMs EMs Sohn, JPET 262: ; 1992

23 Alastair J.J. Wood CYP2C19 Genotype + Intragastric pH Furuta et al., Clin Pharmacol Ther 65: , PlaceboOmeprazole

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

25 Alastair J.J. Wood Reality Population differences due to Genetics Environment Bridging Studies - Ethnicity

26 Alastair J.J. Wood Genetic Polymorphism Two Populations EMs Clearance100L/min PMs Clearance1L/min

27 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

28 Alastair J.J. Wood Dose A 18% < B Rational?

29 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

30 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

31 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

32 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

33 Alastair J.J. Wood

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