Japan Perspective on Japan Perspective on PGt/PGx PGt/PGx

in the Drug Development in the Drug Development and Approval Processand Approval Process

J. Azuma M.D. Osaka University, Osaka, JAPAN

OSAKA UNIVERSITY

22

Non responderNon responder

Asthma 　　　 β2 adrenergic agonist 4 〜 75 5-LO, LTD4

Cancer Various 70 〜 100（ breast,lung,brain) Depression SSRIs, Tricyclics, MAOs 20 〜 40 Diabetes Sulfonylurea, Biguanides, 50 〜 75

GlitazonesDuodenal ulcer H2 antagonists, 20 〜 70 Proton pump inhibitorsHyperlipidemia HMGCoA reductase, 30 〜 75

Resins, Niacin

　 Disease 　 　　 Drug Class 　　　　 Non responder (%)

Pharmacogenomics eds. Kalow, Tyndale, Meyer (p17, Marcel Dekker, May 2001)

33

Paradox of Modern Drug Paradox of Modern Drug DevelopmentDevelopment

● Clinical trials provide evidence of efficacy and safety at usual doses in populationspopulations

● Physicians treat iindividual ndividual patients who can vary widely in their response to drug therapy

Lawrence J. Lesko; International Pharmacogenomics Symposium

Tokyo, Japan April 25, 2003

44

Overview of TalkOverview of Talk

Treatment of tuberculosis with isoniazid and rifampicin

Treatment of chronic heart failure with β-adrenergic receptor blockers

Japan Pharmacogenomics Consortium (JPGC)Pharmacogenetics (PGx)-Pharmacoeconomics (PEx) Working Group

Pharmacogenome Tip Top Inc. (P-TipTop)

5

Treatment of Pulmonary Tuberculosis

•Approximately 20％ of the patients treated with Rifampicin and INA develop hepatotoxicity.

•Metabolic enzyme of INH is NAT2.

•Rifampicin strongly induces many drug metabolizing enzymes.

6

Metabolic pathways of isoniazid

EnzymeAcetylation

Acetylation

Acetyl-

glycineIsonicotinyl

Rifampicin

Acetylhydrazine (AcHz)NH2NHCOCH3

NAT2

(NHCOCH3)2Diacetylhydrazine

N

COOHisoniazid

induction

N

CONHNHCOCH3

N

CONHNH2

NAT2 Hydrazine (Hz)

NH2NH2

Hepatotoxic

Isoniazid (INH) Hydrolysis

NAT2

Hydrolysis

7

Mutation of N-acetyltransferase 2

803

481C→ Ｔ

590G→A

857G→A

845

434

341

282

191G→A

C→T

A→C

A→C

A→G

A→C111T→C

190C→T

499

G→A

759 C→T

* * *** * * *** * * *

ＳＮＰｓ

8

Frequency of the NAT2 genotypes in Frequency of the NAT2 genotypes in patients patients

Genotype

NAT2*4 / *4NAT2*4 / *5NAT2*4 / *6NAT2*4 / *7

NAT2*5 / *5

NAT2*5 / *6

NAT2*5 / *7

NAT2*6 / *6

NAT2*6 / *7

NAT2*7 / *7

n %

RA type (40.3%)

IA type (46.5%)

SA type (13.2%)

46

43415

020742

114

40.3

3.529.813.2

0.01.80.06.13.51.8

100.0

9

Incidence of INH-Rifampicin (RFP) induced Incidence of INH-Rifampicin (RFP) induced hepatotoxicity and NAT2 genotypehepatotoxicity and NAT2 genotype

normal hepatotoxicity

criteria: serum AST and/or ALT > 1.5 x upper limits of normal 　　　　 and 2 x before administration.

Incidence (%)0 20 40 60 80 100

Total(n=114)

RA type(n=46)

SA type(n=15)

IA type(n=53) *

*

* P<0.01

10

Trough plasma concentration of INH and

hydrazine metabolites in relation toNAT2 gene polymorphisms

RAIASA

*p < 0.05 vs RA & IA

mean±SD

(n=29)

(n=31)

(n= 7)

Pla

sma

conc

ent

r ati o

n (

M)

0

2

4

6

8

INH AcHz Hz

**

**

**

11

Hydrazine induced cytotoxicity on HepG2 cells

1 2 3 4 5 6 7 8 9 10 111213

M*5

KpnⅠ*6

TaqⅠ*7

BamHⅠ

2,6,10 : w/w 3,7,11 : w/m4,8,12 : m/m 5,9,13 : HepG2

Genotype of HepG2 　　 NAT2 *5/ *6 　　　　　　 ( slow acetylator )Culture : MEM/Earle’s salt (10% FBS) 5% CO2 -95% 　 Air 37 °C

Stimulus : Hz, AcHz

Incubation time : 48 hour

Assay : AST, ALT, and LDH leakage Cell proliferation

12

Toxic effects of hydrazine on HepG2 cells

Mean±S.E. (n=12) Incu. 48h 　＊ P < 0.05

Cell proliferation ALT

Cont AcHz

Ra

tio to

th

e n

ontr

eate

d co

ntr

ol (

%) ＊

Cont

En

zym

e le

aka

ge

into

the

me

diu

m (

IU/L

) ＊

HzHz AcHz0

100

50

0

10

20

0.3 mM 0.1 mM 0.3 mM 0.1 mM

13

INH(mg/day) 400 100 200

RFP(mg/day) 450 450 300

Case 1（ female 69years)

Day0 20 4030 50 60 70 80 9010

250

300

350

200

150

100

50

0Se

rum

am

ino

tran

sfe

ras

e (

IU/L

)

ASTALT

drug monitoring

Case in SA type

検出菌数（蛍光法） 2+ 1+ ±

発疹のため投与中止

NAT2*6/*6 (SA type)

14

0 5 10 15

5

6

7

4

3

2

1

0

Time after administration (hr)

INH

co

nce

ntr

atio

n (g

/mL

)

400mg/day200mg/day

Plasma INH concentration-time profile observed in patient of case1

Reduced

15

Cases in RA type

INH 400mg/day(po) 　　

+200mg/day(inhalation)

+RFP+SM

Case 5 (male 62years)

: NAT2*4/*4 (RA type)

INH 400mg/day (po)+RFP+SM

Poor Response

Cured

Time after administration (hr)

INH

con

c. (g

/mL)

0 5 10 15

Case 5Mean of RA type(400 mg/day)

2

1

3

1616

INH ＋ RFP

slow acetylator 　 (SA type) 　

　 intermediate acetylator (IA type)

　 rapid acetylator (RA type)

Continue

Chenge regimen

Delayed Cured

INH-RFP induced hepatotoxicityINH-RFP induced hepatotoxicity

Liver Toxicity

RFP:rifampicin

How to Rationalize Dosing

How to Rationalize Dosing ？？

Increase dose

1717

Plasma INH concentration-time profile Plasma INH concentration-time profile

Time after administration (hr)

10

0 5 10 15

1

0.1

0.01

0.001

INH

co

nce

ntr

atio

n (g

/mL

)

RA typeIA typeSA type

Same dosebut different plasma concentrations

(1 – 4 points/person)

Patients (n ) ： 114

Sparse plasma (n ) ： 278

Dose: INH 200 mgat steady state

Therapeutic range

Minimal inhibitory concentration (MIC)

1818

Simulation of dose Simulation of dose adjustment of adjustment of INHINH based on NAT2 genotype based on NAT2 genotype

(preliminary)(preliminary)

200 mg x 2 /day

All types RA-typeI A-typeSA-type

500 mg x 2 /day 250 mg x 2 /day 100 mg x 2 /day

Present Simulated

0.2

3.0

INH

con

c. (g

/mL

)

0 12 24

Css

min

0 12 24

max

hr hr

19

Standard dose of INH

Frequency of slow acetylator(SA-type)

Japan

300 mg/day

400 mg/day(8 mg/kg/day)

(5 mg/kg/day)Europe& USA

Japanese

Caucasians

10 %

50 %

Trou

gh c

onc.

of

INH

(mg/

mL)

MIC0.05-0.2 g/mL

RA-typeIA-typeIA-type + HT

SA-type + HT0 2 4 6 8

Dose (mg/kg)

10

1

0.1

0.01

0.001

n=60

HT: hepatotoxicity

Trough plasma concentration of INH

in relation to NAT2 genotype

2020

BenefitBenefit

◆ 　 Effect on pharmacoeconomics 〈 t.b. 〉

◆ 　 Decrease the incidence of drug resistance in Micobacterium tuberculosis

◆ 　 Decrease the incidence of drug-induced hepatotoxicity

◆ 　 Decrease of relapse rate of pulmonary tubercurosis

Newly diagnosed patients in Japan ＝ about 40,000 persons/year

Incidence of drug-induced hepatotoxicity in Slow acetylator（ about 10% of Japanese) ＝ 100% （ about 4,000 persons/year ）Increase on the cost for remedy followed by drug-induced hepatotoxicity (/year)20,000 yen （ 1day ） ×60 days×4,000 persons ＝ 4.8 billion yen ？Cost for NAT2 genotyping

　　　～ 10,000 yen （ 1time ） × 40,000 persons 　＝ ～ 0.4 billion yen

4.4 billion yen

◆ 　 Inprove therapeutic effect

2121

Clinical trial for genotype based Clinical trial for genotype based chemotherapy against pulmonary tuberculosischemotherapy against pulmonary tuberculosis

Patients with pulmonary tuberculosis

NAT2 genotyping NAT2Gene chip

◆ Multi-center prospective randomized clinical trial

◆ Rationalized dosing of isoniazid based on NAT2 gene polymorphism

◆ Safety, Efficacy, Pharmacoeconomics

SA-typeIA-typeRA-type

2222

Clinical trials for β-blocker therapy in chronic heart failure

MERIT-HF

COPERNICUS

NYHA

II ～ III

IV

metoprolol

carvedilol

Mortality

US Carvedilol II ～ IIIcarvedilol － 65%

CIVIS II IIIbisoprolol － 34%

－ 34%

－ 35%

23

Individual Difference in β-blocker Effect

0

5

10

15

20

25Before

After

(%)

（ 33 例：41.8 ％）

（ 41 例：51.9 ％）

（ 5 例：6.3 ％）

β-bloker （ 79cases ）%FS ±3%

Responde

r

Non-

responder

Bad-

responder

11.8

21.7

14.9 15.0

19.3

12.2

For Individualized Medications

Genotyping

Responder ; improvement of

3 % in the fractional shortening

%FS

24

β1AR Polymorphism

Ser49Gly

Arg389Gly

J Mol Med 2000;78:87-93.

2525

CodonCodon Amino acid Amino acid changechange Function change (in vitro)Function change (in vitro)

ββ1 1 ARAR4949 Ser→GlySer→Gly Increased down regulationIncreased down regulation

389389 Arg→GlyArg→Gly Decreased G-protein couplingDecreased G-protein coupling

ββ2 2 ARAR1616 Arg→GlyArg→Gly Increased down regulationIncreased down regulation

2727 Gln→GluGln→Glu Decreased down regulationDecreased down regulation

αα2c 2c ARAR 322-325322-325 deletiondeletion Reduced agonist binding and Reduced agonist binding and decreased G-protein couplingdecreased G-protein coupling

Adrenergic Receptor PolymorphismsAdrenergic Receptor Polymorphisms

2626

Drug metabolizing enzymes for β-blocker

metoprololbisoprolol

CYP2D6

CYP2D6/3A4/1A2

β-blocker Drug metabolizing enzymes

carvedilol

27

Effect of CYP2D6Effect of CYP2D6**10 allele 10 allele on PK of S-metoprololon PK of S-metoprolol

0

100

200

300

400

500

Conc

entr

atio

n in

pla

sma

(nM

)

0 2 4 6 8 10 12 14Time (hr)

CYP2D6*10/*10

2D6*1/*1

Clin Pharmacol Ther 1999 ; 65 : 402-407

2828

Chronic Heart Failure

βblokerβbloker

responderresponder non-respondernon-responder

CAUSEPlasma Concentration

of β blocker

Function of Target Molecules of β blocker

PolymorphismsAR and Target Molecules

PolymorphismsDrug Metabolizing Enzyme

29

β1AR Ser49Gly and Risk in CHF

Eur Heart J 2000;21:1853-8.

0 1 2 3 4 5

20

40

60

0

p = 0.016

p = 0.12

Follow-up (years)

Risk of end-point (％

)

△

▲

☆

Ser49 homozygotes without b-blockers (n=63)

Gly49 variant without b-blockers (n=28)

Ser49 homozygotes with b-blockers (n=59)

Gly49 variant with b-blockers (n=33)

△

▲

☆

★

★β-blocker is more effectivein Patients with Gly allele

Increased down Increased down regulationregulation

3030

Kaye, DM, et al Pharmacogenetics 　 (2003) 13 ； 379-382

β2 adrenergic receptor

polymorphism

Responder； Improved LVEF by 10% Improved FS by 5%

Ratio of Responders

Gln/Gln

Gln/Glu Glu/Glu

26%

62%

Gln27Glu is a potential determinant for

the response to carvedilol in heart failureDecreased down Decreased down

regulationregulation

3131

Heart failure and Polymorphism Heart failure and Polymorphism ofof α α2c2c ARAR

α2c AR Del322-325

Allele frequencyAllele frequency

CHFCHF healthyhealthy

BleckBleck 0.620.62 0.410.41

WhiteWhite 0.110.11 0.040.04

YellowYellow ?????? ??????

Japanese ? N Engl J Med (2002) 347, 1135-42

（ 2002,10 reported ）

α2C

α2A

Norepinephrine

β1 β3β2

Cardiac-cellmembrane

Sympatheticnerve

α2CDel322-325

Decreased Function in vitro

β １Ａｒｇ３８９ GlyＩｎｃｒｅａｓｅｄFunction in vitro

These two polymorphism of receptors act synergistically to increase the risk

of heart failure in black.

3232

Allelic frequency of adrenergic receptor polymorphismsin healthy and CHF and CHF

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Ser49Gly Arg389Gly Arg16Gly Gln27Glu α2c Del

Allelic

frequency

CHF (n = 36)Healthy (n = 96‐101)

β1 AR β2 AR α2 ｃ AR

Allelic frequency of αAllelic frequency of α2c 2c AR Del322-AR Del322-325 in healthy Japanese is 0.14.325 in healthy Japanese is 0.14.

Black and WhiteBlack and White ：： CHFCHF ＞＞ HealthyHealthy

3333

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Ser49GlyArg389GlyArg16GlyGln27Glu

Responder (n=21)non-Responder (n=13)

Allelic frequency of adrenergic receptor polymorphisms

in Responder and non-ResponderResponder and non-ResponderAllelic

frequency

β1 AR β2 　

ARα2 ｃ AR

α2c Del

Responder ：improvement of 3% in the fractional shortening

3434

Scientific Basis for Using PGt to Scientific Basis for Using PGt to Rationalize DosingRationalize Dosing

Top 27 drugs frequently cited in ADR Top 27 drugs frequently cited in ADR reportsreports59% (16/27) metabolized by at least 59% (16/27) metabolized by at least

one enzyme having poor metabolizer one enzyme having poor metabolizer (PM) genotype(PM) genotype

38% (11/27) metabolized by 38% (11/27) metabolized by CYP 2D6CYP 2D6mainly drugs acting on CNS and mainly drugs acting on CNS and

cardiovascular systemscardiovascular systems

Phillips et al, JAMA, 286 (18), 2001, 2270-2279

3535

Summary of CYP2D6 Summary of CYP2D6 activityactivity

Multiple active genes

*10/ PM gene (about 3 ％ )

High

CaucasiansJapanese

PM PM

hetEM: wt / PM gene

IM

EM

UM

wt / wt （ wild type)

phenotype

EM

Mainly (CYP2D6*5 ）1%>

*10/*10 (about 15 ％ ) hetEM: wt / PM gene

wt / wt （ wild type ）

Ultra Rapid (low frequency ）

activity

5-10%*3,*4,*5 etc

Ultra Rapid （ ethnic difference ）UM

??? ( *2 with -1584CG SNP)

wt /*10

Low

phenotypeGenotype Genotype

3636

Clinical significances of polymorphisms in β-blocker therapy against

Chronic Heart Failure

Patient ： NYHA II or III EF<40%, 1500 patients (multicenter, 300 hospitals ）

Drug ： Carvedilol (2.5mg 、 5mg 、 20mg/day) Endpoint ： Mortality, Cardiovascular death, Mobility

Surrogate Marker : Cardiac functionSub analysis : Genotyping

Directed by A Kitabatake MD, PhD (Hokkaido University)Supported by Japanese Circulation Society

Mega trial of β-Blocker Treatment in Japanese Patients with Chronic Heart Failure (J-CHF)

37

PharmacogenomicsPharmacogenomics: systemic genomic : systemic genomic analysis in populations of treated subjects to analysis in populations of treated subjects to identify variants that predict drug response identify variants that predict drug response

including the occurrence of adverse including the occurrence of adverse reactionsreactions

Potential Use of PGx in Drug Development

Drug Discovery Drug Therapy Drug Selection

New Drug TargetsNew Biomarkers

Rationalize Dosing

Class of Drugs

Cause of Disease Differential Diagnosis

By 2010 By 2005 By 2008

Lawrence J. Lesko International Pharmacogenomics Symposium

Tokyo, Japan April 25, 2003

3838

Overview of TalkOverview of Talk

Treatment of tuberculosis with isoniazid and rifampicin

Treatment of heart failure with β-adrenergic receptor blockers

Japan Pharmacogenomic Consortium (JPGC)Pharmacogenetics (PGx)-Pharmacoeconomics (PEx) Working Group

Pharmacogenome Tip Top Inc. (P-TipTop)

JPGC OutlineJPGC Outline（（ Japan Pharmaco-genomics Consortium)Japan Pharmaco-genomics Consortium)

Rep. Fujisawa Yukio

40

ＪＰＧＪＰＧ CC 　　 BackgroundBackground

Perspective ・ Globalized competition ・ Genomic, ‘tailor-made’ medicine to be realized with Pharmaco-genomics/genetics evolution

Urgent Need to create a better climate for performing quality clinical trials on pharmaco-

genomics/genetics (PG) in drug development as well as in post-marketing Collaboration among pharmaceutical companies

to solve problems and develop techniques

41

Participating companiesParticipating companies

Otsuka Pharmaceutical Co., Ltd. Sanwa Kagaku Kenkyusho Co., Ltd. Shionogi & Co., Ltd. Sumitomo Pharmaceuticals Senju Pharmaceutical Co., Ltd. Dainippon Pharmaceutical Co., Ltd. Takara Bio Inc. Takeda Chemical Industries, Ltd. Tanabe Seiyaku Co., Ltd. Fujisawa Pharmaceutical Co., Ltd.　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　

＊ as of Sep., 2003

42

Research PointsResearch Points

● Technological requirements for PG trials● Correlation analysis method between clinical and genetic data

● Method of selecting genes targeted for analysis

● Standards of ethical review and personal information management

● Analysis of PG trial data and construction of useful database for clinical evaluation

● Analytic engineering to utilize the database

Foundations and Standardization

Pilot study on clinical pharmacology

● Clinical trial to verify a hypothesized relation between marketed drug and genetic polymorphism

43

ＪＰＧＪＰＧ C Action PlanC Action Plan

Jun. Sep. Dec. Mar. Jun. Sep. Dec. Mar. Jun.

2003 2004 2005

Founded on Jul.14

Ethical matters, PG trial groundwork & internal standard

Plan to perform a test study on clinical pharmacology

Building a common DB as well as study DB on CP*

WG-ＩWG-II

WG-III

*Clinical Pharmacology=CP

PG

Clin

ical stud

ysu

pp

ort cen

ter

44

CIOMS The Council for International Organizations of Medical

Sciences

• Established by WHO and UNESCO in 1949• Activities :

– Bioethics– Health Policy, Ethics and Human Values - An

International Dialogue– Drug Development and Use

• Safety requirements for the use of drugs• Assessment, monitoring and reporting of adverse drug

reactions• Reporting and terminology of adverse drug reactions• Ethical criteria for drug promotion• Surveillance and assessment of drug safety data from

clinical trials• Pharmacogenetics and Pharmacoeconomics

– International Nomenclature of Diseases

45

CIOMS Working Group on Pharmacogenetics and Pharmacoeconomics

• Membership: Academia (3), drug regulatory agencies (14) and the

pharmaceutical industry (13) –University of Tokyo, MHLW, Yamanouchi

• Targets: Terminology, impact, cost, regulation, ethics etc. of pharma

cogenomics and pharmacogenetics

• Pharmacoeconomic issues in Pharmacogenetics–Database relating Pharmacogenetics–Regulatory Perspectives–Pharmacogenetics: Unresolved Issues and Barriers to Progress–Ethical Issues–Progress reports regarding pharmacogenetics

CIOMS が作成するレポートは、国際的な強制力は持たないものの、 ICH 等を通じて各国の医薬品行政に影響を及ぼす可能性が強いので、その動向に注意する必要がある。

46

Rational Use of Rational Use of Pharmacogenomics in Drug Pharmacogenomics in Drug

Development and RegulationDevelopment and Regulation Aim: Develop ethical, social and economical infrastructure for

appropriate use of pharmacogenetics and pharmacogenomics Scope: examine and analyze efforts of regulatory authorities a

nd industries relating to pharmacogenetics and pharmacogenomics and establish its proper use in drug development and clinical practice.

Schedule: FY2003 - FY2005 (3 years-term) Budget: 6 million yen (FY2003) Supporter: Ministry of Health, Labor and Welfare Project Leader: Tsutani, Kiichiro (Tokyo University) Participant: Junichi Azuma (Osaka University), Tohru Masui (N

ational Institute of Health Sciences), Hiroshi Gushima (Kurume University), Mieko Tamaoki (Yamanouchi Pharmaceutical)

47

Pharmacogenomic trails in our laboratoryapproved by the ethical committee in Osaka

University

Category Category TitleHeart failureHeart failure 心不全の個別治療のためのゲノム解析に関する臨床研究

AsthmaAsthma ロイコトリエン拮抗薬ﾌﾞﾗﾝｸﾞｶｽﾄにおける薬効の個体差の解明

TuberculosisTuberculosis 薬効ゲノム情報に基づく結核治療の個別適正化プロジェクト

DepressionDepression 精神疾患患者に対する個別化適正薬物投与のための薬物感受性遺伝子に関する研究

ArteriosclerosisArteriosclerosis ホモシステインを標的とした動脈硬化治療法の確立

Adverse event Adverse event 小児におけるアセトアミノフェン副作用発現の個人差の解明

Drug metabolismDrug metabolism 日本人健康男性志願者におけるチトクロム P450を介した薬物代謝能の検討を目的とした臨床薬理試験

SmokingSmoking 有効な禁煙指導を行うための遺伝子多型の解析

Cohort StudyCohort Study 離島における薬物応答性遺伝子多型に関する情報の体系的収集と解析の試み

New Genotyping New Genotyping SystemSystem

新規遺伝子解析システムによる遺伝子多型判定法の開発

4848

PGt/PGx Clinical Study PGt/PGx Clinical Study on going and conducted so on going and conducted so

far far Number of protocol

Collaborate with Original

s or support

Units

CYP2D6 10 Agent Unit for Phase I trial

other metabolic enzyme

3 Agent Unit for Phase I trial

other metabolic enzyme

2 no Unit for Phase I trial

Tuberculosis In progress （ Agent） Public Hospital

Heart Failure In progress （ Agent） University hospital（ Multiple trial）

Depression In progress （ Agent） University hospital

Asthma In progress （ Agent） Public Hospital

Diabetes In progress Public Hospital

Cohort study In progress Local clinic

49

Case 1 Dose-dependency ： Inconsistency of plasma concentration

was observed in dose escalation. 　→ We could explain this phenomenon by different number of the

subjects with decreased CYP450 activity enrolled at different dose groups. (→ Go forward ）

Case 2 Bio-equivalence Study→ We could complete our goal by enrolling small number of

subjects genotyped as same before the trial, for additional formula application or generic drug development.

Case 3 Undesirable contribution of genetic factor → The finding suggested that the candidate compound should be

changed positively to a backup derivative in an early stage. Case 4 Suggestive in vitro data of contribution

polymorphic CYP450→ We could not find the contribution of the genotypes in vivo on

the level of plasma concentration （→ Go forward safely ）

Have genetic testing aided drug development 　 ?? ？

5050

　 Bood samples(I.D.)

Clinical trials

/Treatmentsbased on genetic variationPatients(I.D.)

DoctorsPharmacis

ts

Genotyping

Published Evidence

New Evidencefrom research institute

IT Network

Data Bank on Genetic Variation

Genetic Information Center(I.D.)

･ Process information･ Bioinformatics･ Expect pharmacokinetics/ adverse effects in vivo･ Simulate response in silico

Personalized Medication

right treatment for the right right treatment for the right patient patient at the right time. at the right time.

Patent obtaining

New Drug Discovery & Development

Application of PGx/PGt providing tailored Application of PGx/PGt providing tailored medicines medicines

for individualsfor individuals

薬効ゲノム情報（株）

Creation of database for Creation of database for pharmacogenetic knowledge pharmacogenetic knowledge

5151

52

・ Establish Japan standard for PG study (trial) 　 　 Corporate・ Request cooperation from collaboration medical institutions and administration 　 　 　 　 　 　 　 in working 　 is 　　　・ Found a practical support center indispensable!

Tasks to be coped by JPGCTasks to be coped by JPGC

・ Ethical system (in medical institutions

and industries)

・ IC ・ personal information, Sample

storage

・ Evaluation method on genomic data

Know-how, TechniquesKnow-how, Techniques

・ Screening method of gene analysis

・ Correlation analysis between genetic

　 data and clinical information

・ Finding SNPs with strong correlation

/association 　

TasksTasks

Japan (Internal) Consortium （ JPG ） founded

Better Climate, Standardization

53

JPG Consortium GoalJPG Consortium Goal

● Improve the basic conditions and establish a Japan standard for promoting PG study in development and post-marketing The essential items on Informed Consent and an explanation

　　 　 Method of screening target genes

　　　 Correlation analysis method ・ Clinical evaluation standard

● Found a support center to help companies in performing PG clinical studies with genetic

analysis. 　　Utilities for each member company to perform PG trials, including stored products of consortium activities

54

OrganizationOrganization

Groundwork G.

Domestic interchange

Legal affairs Pilot Study G. International Public Relations

Database Establishment G. Logistics

General Meeting

Steering Committee

Working Group Liaison Group Admin. Group

SecretariatAdvisory Board

55

Concept on the use of JPGC productsConcept on the use of JPGC products

ＪＰＧＣＪＰＧＣ

Co. Ａ

Co. B

Co. C

Co. D

Particip

atio

n

Use o

f the

Institu

tion

Univ. & Medical Institution

Overseas ConsortiumThe more use,

the better inquality and cost

Support ＆ Promotion

Mo

HL

WM

oH

LW

PG study

Support

Center

Standardization ・ Storage of Data & Know-how

Know-how introduction

56

ＴＲＩ ＴＲＩ UtilizationUtilization

● To build a frequency analysis database

on healthy subjects

● To make the database more complete

with the data from pilot studies

● To lay the foundation of the DB, based on

the support center plan

Use of TRI facilities, services and software for linkage analysis

57

Collaboration with Collaboration with ＴＲＴＲＩＩ

the TRI’s goal & role:・ Build data foundation for Translational research from basic research to clinical or practical use ・ Perform studies in cure and care field,

Consortium activities consist with

including public relations about PG, SNPs study and their benefit to promote the

Translational Research.

5858

個別化医療

患者ＢA遺伝子B遺伝子×

レスポンダー

治癒

ゲノム解析

治療法

治癒

レスポンダー

匙加減 ( 質・量）

患者Ａ

B遺伝子× A遺伝子

治療法

薬剤Ｘ

薬剤Ｙ

Drug SelectionRationalize Dosing

Class of Drugs

診断

5959

Translation of PGx to Bedside Translation of PGx to Bedside Medicine: Predict Drug Response in Medicine: Predict Drug Response in

AdvanceAdvance

From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-121

GCCCACCTC

GCCCGCCTC

6060

DNA 自動検査装置 GenelyzerTM の開発