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

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