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
Alastair J.J. Wood
Ethnic Variability in Drug Response
How do we prescribe drugs?
How do we individualize therapy?
Alastair J.J. Wood
Toxicity No EffectOops!Oops!
Too Much Too Little
Dose Dose
No effect
DoseToxicityDose
Alastair J.J. Wood
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 GenomeWhy 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
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
Alastair J.J. Wood
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
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
Alastair J.J. Wood
CYP2C9 Substrates
tolbutamidephenytoinS-warfaringlipizidetamoxifendiclofenacibuprofenpiroxicam
suprofenS-naproxensulfamethoxazoletorsemidelosartanbusipirone
Alastair J.J. Wood
CYP2C9 and Glipizide
Kidd et al., Pharmacogenetics, 9: 71-80, 1999.
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
Alastair J.J. Wood
CYP2C9Reduced (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
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%
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
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 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
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
Alastair J.J. Wood
CYP2C19 Substrates
S-mephenytoinhexobarbitalR-mephobarbitalphenytoindiazepamcitalopram
omeprazolelansoprazolepantoprazole
R-warfarin (8-OH)propranolol (in part)imipramineclomipramineamitryptyllineproguanilteniposidenilutamideindomethacinmoclobemide
Alastair J.J. Wood
Time after Omeprazole (hour)
CYP2C19
PMs
EMs
Sohn, JPET 262: 1195-1202; 1992
Alastair J.J. Wood
CYP2C19 Genotype + Intragastric pH
Furuta et al., Clin Pharmacol Ther 65: 552-561, 1999.
Placebo Omeprazole
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)
Alastair J.J. Wood
Reality
Population differences due to Genetics
Environment
Bridging Studies - Ethnicity
Alastair J.J. Wood
Genetic PolymorphismTwo Populations
EMs Clearance 100L/min
PMs Clearance 1L/min
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
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?
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
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 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
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
Alastair J.J. Wood