The Role of Pharmacist in Education of

2010 FIP PSWC/AAPS
Annual Meeting & Exposition
Tuesday afternoon mini-symposia
The Role of Pharmacist in Education of
Pharmacogenetics and Pharmacogenomics in
Japan
2010.11.16
Toshiyuki Sakaeda
Kyoto University, Japan

The Role of Pharmacist in Education of
Pharmacogenetics & Pharmacogenomics in Japan
‣ Introduction
‣ Package inserts in Japan
‣ Inclusion in routine clinical practice
--- The University of Tokyo Hospital ---
‣ Key problems
‣ Summary

The Role of Pharmacist in Education of
Pharmacogenetics & Pharmacogenomics in Japan
‣ Introduction
‣ Package inserts in Japan
‣ Inclusion in routine clinical practice
--- The University of Tokyo Hospital ---
‣ Key problems
‣ Summary

106,000 patients/year
Estimated number of patients
with fatal adverse drug reaction
in USA, 1994
J.Lazarou, et al., JAMA, 279, 1200-1205, 1998.

Estimated number of patients with
adverse drug reaction in USA, 1994
Serious
Fatal
Inpatients 702,000 63,000
Outpatients 1,547,000 43,000
Overall 2,216,000 106,000
J.Lazarou, et al., JAMA, 279, 1200-1205, 1998.

Estimated number of patients with
Cause of death
adverse drug reaction USA, 1994 in USA, 1994
Heart disease 743,000
Cancer 530,000
Serious
Stroke 150,000
Fatal
Inpatients Pulmonary 702,000 101,000 63,000
Accidents 91,000
Outpatients 1,547,000 43,000
Overall 2,216,000 106,000
J.Lazarou, et al., JAMA, 279, 1200-1205, 1998.

To optimize the pharmacotherapy
‣ To diagnose accurately
‣ To select a right drug for a right patient
‣ To set a right dosage for a right patient
‣ To use as directed
‣ To assess the outcome of pharmacotherapy

To optimize the pharmacotherapy
‣ To diagnose accurately
‣ To select a right drug for a right patient
‣ To set a right dosage for a right patient
‣ To use as directed
‣ To assess the outcome of pharmacotherapy

Pharmacogenetics and pharmacogenomics
‣ Pharmacogenetics - coined in the late 1950s
The study of genetic causes of individual variations
in drug response
‣ Pharmacogenomics - recently coined term
The genome-wide analysis of genetic determinants
of drug efficacy and toxicity
K.C.Lee, et al., J.Am.Pharm.Assoc., 50, e1-e17, 2010.

Plasma concentration ( ng/mL )
Plasma concnetration-time curves of
omeprazole after oral adiministration
1250
1000
750
500
CYP2C19*2/*2 or *2/*3 or *3/*3
CYP2C19*1/*2 or *1/*3
CYP2C19*1/*1
Poor metabolizers
= genetic defect of CYP2C19 activity
250
0
0 4 8 12
Time ( hr )
Extensive metabolizers
T.Sakai et al., Pharm.Res., 18, 721-727, 2001.

Intra-gastric pH
10
9
8
7
6
5
4
3
2
1
Intra-gastric pH after oral administration of
omeprazole in CYP2C19*3/*3
20 mg omeprazole
omeprazole
0
9:00 15:00 21:00 3:00 9:00
meal
Time
20 mg omeprazole
basal
T.Kita et al., Pharm.Res., 18, 615-621, 2001.

Intra-gastric pH
10
9
8
7
6
5
4
3
2
1
Intra-gastric pH after oral administration of
omeprazole in CYP2C19*1/*1
20 mg omeprazole
0
9:00 15:00 21:00 3:00 9:00
meal
Time
20 mg omeprazole
omeprazole
basal
T.Kita et al., Pharm.Res., 18, 615-621, 2001.

CYP2C19-meidtaed activation of
an antiplatelet agent, Clopidogrel
CYP2C19
Clopidogrel
[ prodrug ]
CYP2C19
Active metabolite
‣ Activated by CYPs
‣ Main isoform is CYP2C19.
‣ Active metabolite binds with platelet
ADP receptor via disulfide bridge

CYP2C19 genetic polymorphisms
and clopidogrel effects
Estimated rate (%) of
1) death from any cause,
2) nonfatal myocardial infarction, or
3) stroke
‣ Patients with definite acute
myocardial infarction who were
admitted to ICUs
12
10
8
6
4
2
CYP2C19 *2 or *3 carrier
CYP2C19 *1/*1
p=0.01
‣ Treated with clopidogrel
0
0 90 180 270 360 450
Days
T.Simon et al., N. Engl. J. Med., 360, 363-375, 2009.

The Role of Pharmacist in Education of
Pharmacogenetics & Pharmacogenomics in Japan
‣ Introduction
‣ Package inserts in Japan
‣ Inclusion in routine clinical practice
--- The University of Tokyo Hospital ---
‣ Key problems
‣ Summary

Descriptions in package inserts in Japan
‣ Omeprazole
CYP2C19*2, *3
‣ Clopidogrel
CYP2C19*2, *3
‣ Carbamazepine
HLA-B*1502
‣ Abacavir
HLA-B*1501
blood concentration
active metabolite
Stevens-Johnson, Lyell
Hypersensitivity

Descriptions in package inserts in Japan
‣ Azathioprine
TPMT*3 blood concentration
‣ Mercaptopurine
TPMT*3 blood concentration
‣ Irinotecan
UGT1A1*6, *28 serious adverse events
‣ Warfarin
CYP2C9*3 blood concentration

Package insert of CPT-11 in Japan
‣ Pay attention to individuals harboring UGT1A1*6
or *28 allele, since they are reportedly at increased
risk for serious adverse events (neutropenia) due to
delay in the elimination of an active metabolite,
SN-38.
A large-scale prospective
No recommendation
clinical investigation on
for dose reduction
the effects of dose-reduction

The Role of Pharmacist in Education of
Pharmacogenetics & Pharmacogenomics in Japan
‣ Introduction
‣ Package inserts in Japan
‣ Inclusion in routine clinical practice
--- The University of Tokyo Hospital ---
‣ Key problems
‣ Summary

To include in routine clinical practice
The case of The University of Tokyo Hospital
‣ Much evidence has been accumulating over the last decade.
‣ A part of knowledge has already been translated into diagnostic tools.
‣ It is important to establish “the system”.
Pharmacists can play an important role
in routine clinical practice.

PGx working group in the University of Tokyo Hospital
PGx working group
Clinical Genomics Dept.
Total consultation
Clinical Laboratory
DNA extraction & storage
Genotyping
Clinical Informatics Dept.
Data coding
Information management
Pharmaceutical Dept.
Obtaining of informed consent
PGx information consultation
IRB support
Each of clinical divisions
Patient's enrollment
Exploitation of data

Scheme of outpatient genotyping
1 st visit
Patient
Doctor
PGx testing order
2 nd visit
Patient
Pharmacist
Obtaining of informed consent Blood sampling Genotyping
3 rd visit
Recording
Pharmacist
Pharmacist
Consultation for patient
Consultation for doctor

Personal information confidentiality
Name:Babe Ruth
Patient ID: 1-234-567
PGx ID number is automatically and
randomly coded by computer
Label for PGx testing
PGx ID: 7-654-321

Leaflets for PGx testing
for consultation
with informed consent

Informed consent

The Role of Pharmacist in Education of
Pharmacogenetics & Pharmacogenomics in Japan
‣ Introduction
‣ Package inserts in Japan
‣ Inclusion in routine clinical practice
--- The University of Tokyo Hospital ---
‣ Key problems
‣ Summary

Key problems in Japan
‣ Finite healthcares budgets
1. From 2009.4, national/public health insurance
covers UGT1A1 genotyping
2. Coverage: 20,000 JPY ( = 245 USD / 178 EUR )
3. Cost: 31,500 JPY
Who pays 11,500 JPY

We do need
‣ Infinite healthcares budgets
‣ A diagnostic tool with lower cost ( )
‣ Cost-effective appraisal
‣ Education of citizens and medical staffs

We do need
‣ Infinite healthcares budgets
‣ A diagnostic tool with lower cost ( )
‣ Cost-effective appraisal
‣ Education of citizens and medical staffs
Clinical systems are continuously progressed,
and new intervention must have
an additional value, than current practice.

In the pharmacotherapy
with antidepressant medications
‣ The therapy start with lower dose and the
dose will be continuously elevated until
finding of the best dose for each of
patients.
‣ CYP2D6 genotyping might not be necessary.

For the optimization of
pharmacotherapy with warfarin
‣ A handy-type simple diagnostic tool of INR
has been developed.
‣ How we use VKORC1 and CYP2C9 genetic
information

Finite healthcares budgets might suggest
‣ That this new technology do not have the
power now.
‣ That we have to demonstrate the value,
when compared with current practice.

The Role of Pharmacist in Education of
Pharmacogenetics & Pharmacogenomics in Japan
‣ Introduction
‣ Package inserts in Japan
‣ Inclusion in routine clinical practice
--- The University of Tokyo Hospital ---
‣ Key problems
‣ Summary

Summary
‣ A number of evidences that the genotyping-guided
pharmacotherapy enables us to ensure a certain level
of efficacy and to avoid serious adverse reactions.
‣ A part of knowledge has already been translated into
diagnostic tools.
‣ However in Japan, it is still hard to include this new
technology in routine clinical practice.

Summary
‣ The finite healthcares budgets require demonstrating
that this novel intervention provides an additional
value, when compared with current practice.
‣ In addition to cost-effective appraisal, the education of
this new science and the establishment of medical
system are urgently needed.

Thank you for your attention!

eference

Descriptions in package inserts of CPT-11
‣ in USA
Individuals who are homozygous for the UGT1A1*28
allele are at increased risk for neutropenia following
initiation of CAMPTOSAR treatment. A reduced
initial dose should be considered for patients known
to be homozygous for the UGT1A1*28 allele.