Transcript Frequency of Poor Metabolizers in Different Populations

Alastair J.J. Wood
Ethnic Variability in Drug Response
How do we prescribe drugs?
How do we individualize therapy?
Alastair J.J. Wood
Oops!
Toxicity
No Effect
Too Much
Dose
Too Little
Dose
Toxicity
Dose
Alastair J.J. Wood
No effect
Dose
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 P450’s
Major P450 Content of Human Liver
P4502C9/10
P4502D6
P4502D6
P4501A2
P4502C19
P4502E1
P4502A6
P4502C9
Other
P4502C19
P4502E1
P4502C8
P4501A2
P4503A
Alastair J.J. Wood
P4503A4
P4502B6
Shimada et al, 1994
P4502A6
Polymorphism of Drug Oxidation
 CYP2D6
Debrisoquin/Sparteine
 CYP2C19
Mephenytoin
 CYP2C9
S-warfarin
Alastair J.J. Wood
Frequency of the Defective CYP2C9
Alleles in Different Ethnic Groups
Population
CYP2C9*2
CYP2C9*3
CYP2C9*4
CYP2C9*5
Caucasian-American
12.3%
5.6%
0%
0%
Hispanic-American
12.0%
3.4%
0%
0.5%
African-American
2.5%*
1.8%
0%
1.6%
Chinese
0%*
4.1%
0%
0%
Japanese
0%*
0%
0%
0%
* P < 0.001
Alastair J.J. Wood
CYP2C9 Substrates
tolbutamide
phenytoin
S-warfarin
glipizide
tamoxifen
diclofenac
ibuprofen
piroxicam
Alastair J.J. Wood
suprofen
S-naproxen
sulfamethoxazole
torsemide
losartan
busipirone
CYP2C9 and Glipizide
Alastair J.J. Wood
Kidd et al., Pharmacogenetics, 9: 71-80, 1999.
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
Alastair J.J. Wood
CYP2C9
Reduced (S)-Warfarin Clearance in Heterozygotes
Takahashi, CPT, 1998
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
Alastair J.J. Wood
Warfarin Dose and Genotype
Genotype (%)
< 1.5 mg/day
> 1.5 mg/day
Community
CYP2C9 *1/*1
19%
62%
60%
*1/*2
*1/*3
*2/*3
*2/*2
*3/*3
33%
28%
14%
6%
0%
17%
19%
0%
2%
0%
20%
17%
2%
0%
1%
Lancet 353: 717; 1999
Alastair J.J. Wood
< 1.5 mg/day
> 1.5 mg/day
INR > 4 at Induction
56%
17%
Minor bleeds
5.3%
1.9%
8.3%
2.3%
(per person years)
Major bleeds
(per person years)
Lancet 353: 717; 1999
Alastair J.J. Wood
Genetic Causes of Abnormal
Metabolism Within a Phenotype
 Abnormal alleles
 Gene duplication
Alastair J.J. Wood
CYP2D6 - Effects of Gene Duplication
Dalen et al., 1998.
Alastair J.J. Wood
Genetic Polymorphism
CYP2C19
Index drug: Mephenytoin (R and S)
 S-hydroxylation of mephenytoin deficient
in PM’s
Alastair J.J. Wood
Frequency of CYP2C19 Poor Metabolizers
Phenotype
Africans
African-Americans
Caucasians
Chinese
Japanese
Koreans
Amerindians
Alastair J.J. Wood
4.1
1.4
2.8
13.6
20.3
13.7
Genotype
3.8
3.3
2.1
13.8
17.0
16.8
5.7
Frequency of CYP2C19 Poor Metabolizers %
Phenotype
Blacks
Caucasians
Chinese
Japanese*
Koreans*
Alastair J.J. Wood
3.9
2.8
13.6
20.3
13.7
Genotype
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
CYP2C19 Substrates
S-mephenytoin
hexobarbital
R-mephobarbital
phenytoin
diazepam
citalopram
omeprazole
lansoprazole
pantoprazole
Alastair J.J. Wood
R-warfarin (8-OH)
propranolol (in part)
imipramine
clomipramine
amitryptylline
proguanil
teniposide
nilutamide
indomethacin
moclobemide
CYP2C19
l PMs
 EMs
Time after Omeprazole (hour)
Alastair J.J. Wood
Sohn, JPET 262: 1195-1202; 1992
CYP2C19 Genotype + Intragastric pH
Placebo
Omeprazole
Furuta et al., Clin Pharmacol Ther 65: 552-561, 1999.
Alastair J.J. Wood
H. pylori Cure Rate Based on CYP2C19 Genotype
Total cure rate = 52% (n=62)
100
Percent cure rate
90
80
70
60
50
40
30
20
10
0
wt/wt
(n=28)
wt/m1
wt/m2
(n=25)
Omeprazole 20 mg/day for 6-8 weeks
Amoxicillin 2000 mg/day for 2 weeks
Alastair J.J. Wood
m1/m2
m1/m1
(n=9)
T. Furuta et al., Ann. Int. Med., 129: 1027-1030, 1998
Bridging Studies - Ethnicity
Reality
 Population differences due to
 Genetics
 Environment
Alastair J.J. Wood
Genetic Polymorphism
Two Populations
 EMs Clearance 100L/min
 PMs Clearance 1L/min
Alastair J.J. Wood
Ethnic Differences in Drug Clearance
Cl
Frequency
Frequency
Population A
Population B
Extensive
Metabolizer
100L/min
80%
98%
Poor
Metabolizer
1L/min
20%
2%
Mean Clearance
Alastair J.J. Wood
80.2 L/min
98L/min
Mean Clearance (L/min)
100
Dose A 18% < B
75
50
Rational?
25
0
Population A
Population B
Population A
Population B
100
Clearance (L/min)
Clearance (L/min)
100
10
1
0.1
10
1
0.1
0
20
Alastair J.J. Wood
40
60
Percent
80
100
0
10 20 30 40 50 60 70 80 90 100
Percent
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
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
No
Ethnic difference will be
predicted
Ethnic difference suggested?
No
Stop
Yes
Further studies needed?
Yes
Require genotype/
phenotype matching
Alastair J.J. Wood
No
Stop
Unrecognized
genotype
Environmental
factors
Require genotype/
phenotype matching
Genotypes, Variability and Bridging
Studies
 Science has advanced
 Ethnic genotypic variability defined
 Opportunity to rethink strategy
 Need to develop new paradigm
Alastair J.J. Wood
Alastair J.J. Wood