Japan Perspective on PGt/PGx
in the Drug Development
and Approval Process
J. Azuma M.D.
Osaka University, Osaka, JAPAN
OSAKA UNIVERSITY
Non responder
Disease
Asthma
Drug Class
Non responder (%)
β2 adrenergic agonist
5-LO, LTD4
Cancer
Various
(breast,lung,brain)
Depression
SSRIs, Tricyclics, MAOs
Diabetes
Duodenal ulcer
Hyperlipidemia
4〜75
70〜100
20〜40
Sulfonylurea, Biguanides, 50〜75
Glitazones
H2 antagonists,
20〜70
Proton pump inhibitors
HMGCoA reductase,
30〜75
Resins, Niacin
2
Pharmacogenomics eds. Kalow, Tyndale, Meyer (p17, Marcel Dekker, May 2001)
Paradox of Modern Drug Development
●
●
Clinical trials provide evidence of
efficacy and safety at usual doses
in populations
Physicians treat individual patients
who can vary widely in their
response to drug therapy
3
Lawrence J. Lesko; International Pharmacogenomics Symposium
Tokyo, Japan April 25, 2003
Overview 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)
4
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.
5
Metabolic pathways of isoniazid
NAT2
Acetylation
CONHNHCOCH3
N
Acetylisoniazid
Hydrolysis
NH2NHCOCH3
Acetylhydrazine (AcHz)
NAT2
(NHCOCH3)2
Diacetylhydrazine
CONHNH2
N
Isoniazid
(INH)
Rifampicin
Enzyme
induction
Hydrolysis
COOH
N Acetylation
NAT2
Isonicotinyl
glycine
NH2NH2
Hydrazine (Hz)
Hepatotoxic
6
Mutation of N-acetyltransferase 2
T→C G→A
111 191
A→C
434
A→C
G→A
341
499
759 C→T
803 A→G
845 A→C
* ** * * * * * * ****
190
282
C→T C→T
481 590 857
C→T G→A G→A
SNPs
7
Frequency of the NAT2 genotypes in patients
Genotype
n
%
NAT2*4 / *4
46
40.3
RA type (40.3%)
NAT2*4
NAT2*4
NAT2*4
NAT2*5
NAT2*5
NAT2*5
NAT2*6
NAT2*6
NAT2*7
4
34
15
3.5
29.8
13.2
IA type (46.5%)
0
2
0
7
4
2
0.0
1.8
0.0
6.1
3.5
1.8
114
100.0
/
/
/
/
/
/
/
/
/
*5
*6
*7
*5
*6
*7
*6
*7
*7
SA type (13.2%)
8
Incidence of INH-Rifampicin (RFP) induced
hepatotoxicity and NAT2 genotype
Total
(n=114)
RA type
(n=46)
IA type
(n=53)
*
SA type
*
(n=15)
0
20
40
60
80
Incidence (%)
normal
100
* P<0.01
hepatotoxicity
criteria: serum AST and/or ALT > 1.5 x upper limits of normal
and 2 x before administration.
9
Plasma concentration (mM)
Trough plasma concentration of INH and
hydrazine metabolites in relation to
NAT2 gene polymorphisms
8
*
*
*
*
*
*
6
RA (n=29)
IA (n=31)
SA (n= 7)
*p < 0.05 vs RA & IA
mean±SD
4
2
0
INH
AcHz
Hz
10
Hydrazine induced cytotoxicity
on HepG2 cells
*5
M KpnⅠ
*6
*7
TaqⅠ BamHⅠ
1 2 3 4 5 6 7 8 9 10 111213
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
2,6,10 : w/w 3,7,11 : w/m
4,8,12 : m/m
5,9,13 : HepG2
Assay :
AST, ALT, and LDH leakage
Cell proliferation
11
Toxic effects of hydrazine on HepG2 cells
100
50
0
Cont
AcHz
Hz
*
ALT
Enzyme leakage
into the medium ( IU/L )
*
Ratio to
the nontreated control (%)
Cell proliferation
20
10
0
Cont
0.3 mM 0.1 mM
Mean±S.E. (n=12) Incu. 48h
AcHz
Hz
0.3 mM 0.1 mM
*P
< 0.05
12
Serum aminotransferase (IU/L)
Case in SA type
Case 1(female 69years)
350
300
drug monitoring
AST
ALT
250
200
150
100
NAT2*6/*6 (SA type)
50
0
0
10
20
30
40
50
60
70
80
INH
(mg/day)
400
100
RFP
90
Day
200
発疹のため投与中止
(mg/day)
450
検出菌数
(蛍光法)
2+
450
300
1+
±
13
INH concentration (mg/mL)
Plasma INH concentration-time profile
observed in patient of case1
7
6
400mg/day
200mg/day
5
Reduced
4
3
2
1
0
0
5
10
15
Time after administration (hr)
14
Cases in RA type
Case 5 (male 62years)
Poor Response
INH 400mg/day (po)
+RFP+SM
Cured
INH 400mg/day(po)
+200mg/day(inhalation)
+RFP+SM
INH conc. (mg/mL)
: NAT2*4/*4 (RA type)
3
Case 5
2
Mean of RA type
(400 mg/day)
1
0
5
10
15
Time after administration (hr)
15
INH-RFP induced hepatotoxicity
INH+RFP
slow acetylator
intermediate acetylator
rapid acetylator
(SA type)
(IA type)
(RA type)
Liver
Toxicity
Chenge regimen
Delayed
Continue
Increase dose
Cured
16
RFP:rifampicin
Plasma INH concentration-time profile
INH concentration (mg/mL)
Patients (n ):114
10
Sparse plasma (n ):278
(1 – 4 points/person)
1
Dose: INH 200 mg
at steady state
0.1
0.01
0.001
0
Same dose
but different
plasma concentrations
RA type
IA type
SA type
Therapeutic range
5
10
15
Time after administration (hr)
Minimal inhibitory
concentration17(MIC)
Simulation of dose adjustment of INH
based on NAT2 genotype (preliminary)
INH conc. (mg/mL)
Present
Simulated
3.0
Css
max
0.2
min
0
12
24 hr
All types
200 mg x 2 /day
0
12
24 hr
RA-type 500 mg x 2 /day
I A-type 250 mg x 2 /day
SA-type 100 mg x 2 /day
18
Trough plasma concentration of INH
in relation to NAT2 genotype
Japan
Europe
& USA
400 mg/day
(8 mg/kg/day)
300 mg/day
(5 mg/kg/day)
Frequency of slow acetylator
(SA-type)
Japanese
Caucasians
10 %
50 %
Trough conc. of INH (mg/mL)
Standard dose of INH
10
n=60
1
MIC
0.05-0.2 mg/mL
0.1
RA-type
IA-type
IA-type + HT
SA-type + HT
0.01
0.001
0
2
4
6
Dose (mg/kg)
8
HT: hepatotoxicity
19
Benefit
◆ Decrease the incidence of drug-induced hepatotoxicity
◆ Inprove therapeutic effect
◆ Decrease the incidence of drug resistance in
Micobacterium tuberculosis
◆ Decrease of relapse rate of pulmonary tubercurosis
◆ Effect on pharmacoeconomics〈t.b.〉
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
20
Clinical trial for genotype based chemotherapy against
pulmonary tuberculosis
◆ Multi-center prospective randomized clinical trial
◆ Rationalized dosing of isoniazid based on NAT2 gene
polymorphism
◆ Safety, Efficacy, Pharmacoeconomics
Patients with pulmonary tuberculosis
NAT2
Gene chip
NAT2 genotyping
RA-type
IA-type
SA-type
21
Clinical trials for β-blocker therapy
in chronic heart failure
NYHA
Mortality
US Carvedilol
carvedilol
II~III
-65%
CIVIS II
bisoprolol
III
-34%
MERIT-HF
metoprolol
II~III
-34%
COPERNICUS
carvedilol
IV
-35%
22
Individual Difference in β-blocker Effect
β-bloker(79cases)
%FS ±3%
%FS
(33例:41.8%)
(41例:51.9%)
Responder ; improvement of
3 % in the fractional shortening
(5例:6.3%)
(%) 25
Before
20
21.7
After
19.3
15
14.9
10
15.0
12.2
11.8
5
0
Responder
Non-responder Bad-responder
For Individualized Medications
Genotyping
23
β1AR Polymorphism
Ser49Gly
Arg389Gly
24
J Mol Med 2000;78:87-93.
Adrenergic Receptor Polymorphisms
β1 AR
Codon
Amino acid
change
Function change (in vitro)
49
Ser→Gly
Increased down regulation
389
Arg→Gly
Decreased G-protein coupling
16
Arg→Gly
Increased down regulation
27
Gln→Glu
Decreased down regulation
deletion
Reduced agonist binding and
decreased G-protein coupling
β2 AR
α2c AR
322-325
25
Drug metabolizing enzymes
for β-blocker
β-blocker
metoprolol
bisoprolol
carvedilol
Drug metabolizing enzymes
CYP2D6
CYP2D6/3A4/1A2
26
Effect of CYP2D6*10 allele
on PK of S-metoprolol
Concentration in plasma (nM)
500
CYP2D6*10/*10
400
300
200
100
2D6*1/*1
0
0
2
4
6
8
10
12
14
Time (hr)
Clin Pharmacol Ther 1999 ; 65 : 402-407 27
Chronic Heart
Failure
βbloker
responder
non-responder
CAUSE
Plasma Concentration
of β blocker
Function of Target
Molecules of β blocker
Polymorphisms
Drug Metabolizing Enzyme
Polymorphisms
AR and Target Molecules
28
β1AR Ser49Gly and Risk in CHF
△ Ser49 homozygotes without b-blockers (n=63)
▲ Gly49 variant without b-blockers (n=28)
☆ Ser49 homozygotes with b-blockers (n=59)
Risk of end-point (%)
60
★ Gly49 variant with b-blockers (n=33)
△
p = 0.12
40
☆
▲
p = 0.016
20
0
★ effective
β-blocker is more
in Patients with Gly allele
0
1
2
3
4
5
Follow-up (years)
Increased down regulation
Eur Heart J 2000;21:1853-8.
29
β2 adrenergic receptor polymorphism
Ratio of Responders
Gln/Gln
Gln/Glu
26%
Glu/Glu
62%
Responder; Improved LVEF by 10%
Improved FS by 5%
Gln27Glu is a potential determinant for
the response to carvedilol in heart failure
Decreased down regulation
30
Kaye, DM, et al Pharmacogenetics (2003) 13;379-382
Heart failure and Polymorphism
of α2c AR
α2CDel322-325
 2A
Decreased Function in vitro
α2C
Sympathetic
nerve
α2c AR Del322-325
Allele frequency
Norepinephrine
1
CHF
healthy
Bleck
0.62
0.41
White
0.11
0.04
Yellow
???
???
Cardiac-cell
membrane
2
3
(2002,10
β1Arg389Gly
Increased
Function in vitro
These two polymorphism of
receptors act synergistically
to increase the risk
of heart failure in black.
reported)
Japanese ?
31
N Engl J Med (2002) 347, 1135-42
Allelic frequency of adrenergic receptor
polymorphisms
in healthy and CHF
0.7
Allelic frequency
0.6
CHF (n = 36)
Healthy (n = 96‐101)
Allelic frequency of α2c AR Del322325 in healthy Japanese is 0.14.
0.5
0.4
Black and White:CHF>Healthy
0.3
0.2
0.1
0
Ser49Gly
Arg389Gly
β1 AR
Arg16Gly
Gln27Glu
β2 AR
α2c Del
α2c AR
32
Allelic frequency of adrenergic
receptor polymorphisms
in Responder and non-Responder
0.7
Allelic frequency
0.6
Responder (n=21)
non-Responder (n=13)
0.5
0.4
Responder:
improvement of 3%
in the fractional shortening
0.3
0.2
0.1
0
Ser49Gly Arg389Gly Arg16Gly Gln27Glu α2c Del
β1 AR
β2 AR
α2c AR
33
Scientific Basis for Using PGt to
Rationalize Dosing

Top 27 drugs frequently cited in ADR
reports
59% (16/27) metabolized by at least one
enzyme having poor metabolizer (PM) genotype
 38% (11/27) metabolized by CYP 2D6

 mainly
drugs acting on CNS and cardiovascular
systems
Phillips et al, JAMA, 286 (18), 2001, 2270-2279
34
Summary of CYP2D6 activity
Japanese
Caucasians
activity
Genotype
phenotype
Low
PM
1%>
IM
EM
UM
High
Mainly (CYP2D6*5 )
*10/
PM gene (about 3%)
*10/*10
(about 15%)
hetEM: wt / PM gene
wt /*10
phenotype
PM
5-10%
*3,*4,*5 etc
??? ( *2 with -1584CG SNP)
EM
wt / wt (wild type)
Ultra Rapid (low frequency)
Genotype
hetEM: wt / PM gene
wt / wt (wild type)
UM
Ultra Rapid
(ethnic difference)
Multiple active genes
35
Clinical significances of polymorphisms
in β-blocker therapy against
Chronic Heart Failure
Mega trial of β-Blocker Treatment in Japanese Patients with Chronic
Heart Failure (J-CHF)
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 function
Sub analysis : Genotyping
Directed by A Kitabatake MD, PhD (Hokkaido University)
Supported by Japanese Circulation Society
36
Potential Use of PGx in Drug Development
Pharmacogenomics: systemic genomic analysis in
populations of treated subjects to identify variants
that predict drug response including the occurrence of
adverse reactions
Cause of Disease
Drug Discovery
By 2010
New Drug Targets
New Biomarkers
Differential Diagnosis
Drug Therapy
By 2005
Rationalize Dosing
Drug Selection
By 2008
Class of Drugs
Lawrence J. Lesko International Pharmacogenomics Symposium
37
Tokyo, Japan April 25, 2003
Overview of Talk





Treatment of tuberculosis with isoniazid
and rifampicin
Treatment of heart failure with βadrenergic receptor blockers
Japan Pharmacogenomic Consortium (JPGC)
Pharmacogenetics (PGx)-Pharmacoeconomics
(PEx) Working Group
Pharmacogenome Tip Top Inc. (P-TipTop)
38
JPGC Outline
(Japan Pharmaco-genomics Consortium)
Rep. Fujisawa Yukio
JPGC Background
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 pharmacogenomics/genetics (PG) in drug development
as well as in post-marketing
Collaboration among pharmaceutical companies
to solve problems and develop techniques 40
Participating 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
41
of Sep., 2003
Research Points
Foundations and Standardization
●
●
●
●
●
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
Pilot study on clinical pharmacology
●
Clinical trial to verify a hypothesized relation between marketed
42
drug and genetic polymorphism
JPGC Action Plan
2003
Jun.
Sep.
2004
Dec.
Mar.
Jun.
2005
Sep.
Dec.
Mar.
Jun.
Founded on Jul.14
WG-II Plan to perform a test study on clinical pharmacology
WG-III Building a common DB as well as study DB on CP*
*Clinical Pharmacology=CP
43
PG Clinical study
support center
WG-I Ethical matters, PG trial groundwork & internal standard
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
44
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
pharmacogenomics and pharmacogenetics
• Pharmacoeconomic issues in Pharmacogenetics
–Database relating Pharmacogenetics
–Regulatory Perspectives
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
–Pharmacogenetics: Unresolved Issues and Barriers to Progress
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
–Ethical Issues
45
いので、その動向に注意する必要がある。
–Progress reports regarding pharmacogenetics
Rational Use of Pharmacogenomics in
Drug Development and Regulation
Aim: Develop ethical, social and economical infrastructure for
appropriate use of pharmacogenetics and pharmacogenomics
 Scope: examine and analyze efforts of regulatory authorities and
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
(National Institute of Health Sciences), Hiroshi Gushima (Kurume
University), Mieko Tamaoki (Yamanouchi Pharmaceutical)

46
Pharmacogenomic trails in our laboratory
approved by the ethical committee in Osaka University
Category
Heart failure
Title
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
Asthma
ロイコトリエン拮抗薬ブラングカストにおける薬効の個体差の解明
Tuberculosis
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
Depression
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
Arteriosclerosis
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
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 metabolism
Smoking
Cohort Study
New Genotyping System
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
有効な禁煙指導を行うための遺伝子多型の解析
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
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
47
PGt/PGx Clinical Study
on going and conducted so far
Number of
protocol
Collaborate with
Originals
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
48
Have genetic testing aided drug
development ???
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)
49
Application of PGx/PGt providing tailored medicines
for individuals
Creation of database for
pharmacogenetic knowledge
Bood samples
(I.D.)
Clinical trials
/Treatments
based on
genetic
variation
Patients
(I.D.)
Genotyping
Published
Evidence
New Evidence
from research
institute
Patent obtaining
Data Bank
on Genetic Variation
Genetic Information Center
(I.D.)
・Process information
・Bioinformatics
・Expect pharmacokinetics/
adverse effects in vivo
・Simulate response in silico
New Drug Discovery
& Development
Personalized Medication
Doctors
Pharmacists
IT Network
right treatment for the right patient
at the right time.
50
薬効ゲノム情報(株)
51
Tasks to be coped by JPGC
Better Climate, Standardization
・Ethical system (in medical institutions
and industries)
・IC・personal information, Sample storage
・Evaluation method on genomic data
Know-how, Techniques
・Screening method of gene analysis
・Correlation analysis between genetic
data and clinical information
・Finding SNPs with strong correlation
/association
Tasks
・ Establish Japan standard for PG study (trial)
・ Request cooperation from
medical institutions and administration
・ Found a practical support center
Corporate
collaboration
in working is
indispensable!
Japan (Internal) Consortium(JPG)founded
52
JPG 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
53
Organization
General Meeting
Steering Committee
Advisory Board
Working Group
Secretariat
Liaison Group
Admin. Group
Groundwork G.
Domestic interchange
Legal affairs
Pilot Study G.
International
Public Relations
Database Establishment G.
Logistics
54
Concept on the use of JPGC products
Standardization ・Storage of Data & Know-how
Support &Promotion
Univ. & Medical Institution
Co. A
Co. C
Co. D
Overseas Consortium
Know-how
introduction
Use of the
Institution
Participation
MoHLW
JPGC
Co. B
PG study
Support
Center
The more use,
the better in
quality and cost
55
TRI Utilization
Use of TRI facilities, services and software
for linkage analysis
● 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
56
Collaboration with TRI
Consortium activities consist with
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,
including public relations about PG, SNPs
study and their benefit to promote the
Translational Research.
57
Drug Selection
個別化医療
Rationalize Dosing
診断
ゲ
ノ
ム
解
析
患者A
×
A遺伝子
治
療
法
薬剤X
レスポンダー
B遺伝子
Class
of Drugs
匙加減 (質・量)
患者B
×
治
癒
A遺伝子
B遺伝子
治
療
法
薬剤Y
治
癒
レスポンダー
58
Translation of PGx to Bedside Medicine:
Predict Drug Response in Advance
GCCCGCCTC
GCCCACCTC
59
From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-121
DNA自動検査装置GenelyzerTMの開発
60
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