alastair j.j. wood. ethnic variability in drug response how do we prescribe drugs? how do we...
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Alastair J.J. Wood
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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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Alastair J.J. Wood
Toxicity No EffectOops!Oops!
Too Much Too Little
Dose Dose
No effect
DoseToxicityDose
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Alastair J.J. Wood
Ethnic Variability and Bridging Studies
We recognize that:
One dose does not fit all
But - What to do?
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Alastair J.J. Wood
In the Age of the GenomeWhy Do People Respond Differently to Drugs?
Variability in:- Drug metabolism genotype Drug transporter genotype
Drug receptor genotype
Drug/drug/environment /genotype interactions
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Alastair J.J. Wood
Drug Oxidation - Major Route of Drug Metabolism
Family of enzymes (CYPs) in liver
P4502D6
Other
P4501A2
P4502A6P4502B6
P4503A4
P4502C8
P4502C9
P4502C19 P4502E1P4502D6 P4501A2
P4502A6
P4503A
P4502C9/10
P4502C19
P4502E1
Proportion of Pharmaceuticals Metabolized by Individual Cytochrome P450’s
Major P450 Content of Human Liver
Shimada et al, 1994
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Alastair J.J. Wood
Polymorphism of Drug Oxidation
CYP2D6 Debrisoquin/Sparteine
CYP2C19 Mephenytoin
CYP2C9 S-warfarin
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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
Hispanic-American
African-American
Chinese
Japanese
12.3%
12.0%
2.5%*
0%*
0%*
5.6%
3.4%
1.8%
4.1%
0%
0%
0%
0%
0%
0%
0%
0.5%
1.6%
0%
0%
* P < 0.001
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Alastair J.J. Wood
CYP2C9 Substrates
tolbutamidephenytoinS-warfaringlipizidetamoxifendiclofenacibuprofenpiroxicam
suprofenS-naproxensulfamethoxazoletorsemidelosartanbusipirone
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Alastair J.J. Wood
CYP2C9 and Glipizide
Kidd et al., Pharmacogenetics, 9: 71-80, 1999.
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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
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Alastair J.J. Wood
CYP2C9Reduced (S)-Warfarin Clearance in Heterozygotes
Takahashi, CPT, 1998
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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
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Alastair J.J. Wood
Warfarin Dose and Genotype
Lancet 353: 717; 1999
Genotype (%)
CYP2C9 *1/*1*1/*1
*1/*1/*2*2*1/*1/*3*3*2*2//*3*3*2*2//*2*2*3*3//*3*3
< 1.5 mg/day
19%19%
33%33%28%28%14%14% 6%6% 0%0%
> 1.5 mg/day
62%62%
17%17%19%19% 0%0% 2%2% 0%0%
Community
60%60%
20%20%17%17% 2%2% 0%0% 1%1%
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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
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Alastair J.J. Wood
Genetic Causes of Abnormal Metabolism Within a Phenotype
Abnormal alleles Gene duplication
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Alastair J.J. Wood
CYP2D6 - Effects of Gene Duplication
Dalen et al., 1998.
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Alastair J.J. Wood
Genetic Polymorphism
CYP2C19
Index drug: Mephenytoin (R and S)
S-hydroxylation of mephenytoin deficient in PM’s
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Alastair J.J. Wood
Frequency of CYP2C19 Poor MetabolizersFrequency of CYP2C19 Poor Metabolizers
AfricansAfrican-AmericansCaucasiansChinese JapaneseKoreansAmerindians
4.1 1.4 2.813.6 20.313.7
3.8 3.3 2.113.8 17.016.8 5.7
Phenotype Genotype
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Alastair J.J. Wood
Frequency of CYP2C19 Poor Metabolizers %Frequency of CYP2C19 Poor Metabolizers %
BlacksCaucasiansChinese Japanese*Koreans*
3.9 2.813.6 20.313.7
3.7 2.113.8 17.016.8
Phenotype Genotype
Annual Review of Pharmacology & Toxicology 41:815-850, 2001* British Journal of Pharmacology 48:402-408, 1999
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Alastair J.J. Wood
CYP2C19 Substrates
S-mephenytoinhexobarbitalR-mephobarbitalphenytoindiazepamcitalopram
omeprazolelansoprazolepantoprazole
R-warfarin (8-OH)propranolol (in part)imipramineclomipramineamitryptyllineproguanilteniposidenilutamideindomethacinmoclobemide
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Alastair J.J. Wood
Time after Omeprazole (hour)
CYP2C19
PMs
EMs
Sohn, JPET 262: 1195-1202; 1992
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Alastair J.J. Wood
CYP2C19 Genotype + Intragastric pH
Furuta et al., Clin Pharmacol Ther 65: 552-561, 1999.
Placebo Omeprazole
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Alastair J.J. Wood
H. pylori Cure Rate Based on CYP2C19 Genotype
Omeprazole 20 mg/day for 6-8 weeksAmoxicillin 2000 mg/day for 2 weeks
T. Furuta et al., Ann. Int. Med., 129: 1027-1030, 1998
0
10
20
30
40
50
60
70
80
90
100
wt/wt(n=28)
wt/m1wt/m2(n=25)
m1/m2m1/m1
(n=9)
Per
cen
t cu
re r
ate
Total cure rate = 52% (n=62)
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Alastair J.J. Wood
Reality
Population differences due to Genetics
Environment
Bridging Studies - Ethnicity
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Alastair J.J. Wood
Genetic PolymorphismTwo Populations
EMs Clearance 100L/min
PMs Clearance 1L/min
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Alastair J.J. Wood
Ethnic Differences in Drug Clearance
Extensive Metabolizer
PoorMetabolizer
Mean Clearance
Cl
100L/min
1L/min
FrequencyPopulation A
80%
20%
FrequencyPopulation B
98%
2%
80.2 L/min 98L/min
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Alastair J.J. Wood
Population A Population B0
25
50
75
100
Mea
n C
lear
ance
(L
/min
)
Population A
0 20 40 60 80 1000.1
1
10
100
Percent
Cle
ara
nc
e (
L/m
in)
Population B
0 10 20 30 40 50 60 70 80 90 1000.1
1
10
100
Percent
Cle
ara
nc
e (
L/m
in)
Dose A 18% < B
Rational?
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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 dose—not appropriate to either population
Does not improve safety
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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
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Alastair J.J. Wood
Ethnicity in Drug DevelopmentDefine genotype
DispositionResponse
Ethnic differences in genotype distribution?
Yes
Ethnic difference will bepredicted
Further studies needed?
No
Ethnic difference suggested?
Require genotype/phenotype matching
YesUnrecognized
genotype
NoNo
StopStop
NoNo
StopStop
Yes
Environmentalfactors
Require genotype/phenotype matching
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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
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Alastair J.J. Wood