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

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

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

5. 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. 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

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

8. 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

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

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

11. 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

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

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

14. 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

15. < 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

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

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

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

19. 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

20. 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: , 2001
* British Journal of Pharmacology 48: , 1999 14

21. 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

22. CYP2C19 l PMs ¡ EMs Time after Omeprazole (hour)
Sohn, JPET 262: ; 1992

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

24. 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: , 1998

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

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

27. 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

28. Dose A 18% < B
Rational?

29. 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

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

31. 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

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