1. Prof. Yusuke Tanigawara Keio University Hospital Tokyo, Japan
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
3rd Kitasato Harvard Symposium
2 October 2002
Simultaneous/Worldwide Development Strategies : New Challenges New Approaches of Dose Range Finding
Prof. Yusuke Tanigawara
Keio University Hospital
Tokyo, Japan

2. E=f(C(t), S) Drug Action > E=f(Dose, S)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Drug Action
E=f(C(t), S)
> E=f(Dose, S)

3. Pharmacokinetics (PK) Pharmacodynamics (PD) Dose PK data PD data
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
Pharmacokinetics
(PK)
3rd Kitasato Harvard Symposium
2002/10/2
Pharmacodynamics
(PD)
Dose
&
Dosage
Regimen
Plasma
Concen-
tration
Site of
action
Response
Time
Concentration
Dose
PK data
Response
Concentration (Exposure)
PD data
Efficacy
Toxicity
©Y.Tanigawara

4. “New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Why PK/PD are needed.
Human PK/PD, especially in patients, are important drug information.
PK/PD provide a scientific framework for dose/dosage regimen vs concentrations vs response relationships.
Factors affecting PK/PD are considered when dose is individualized for special populations such as geriatrics and organ dysfunction.
PK/PD can be a “bridging” tool for introducing to new indications, new dosage forms, or new populations.

5. Development Phases and Types of Study (ICH E8)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Development Phases and Types of Study (ICH E8)
Therapeutic Use
Therapeutic
Confirmatory
PK or PK/PD study
in Patients
Therapeutic
Exploratory
Human
Pharmacology II
III IV I
Phases of Development

6. Factors That Can Cause the Individual Variability in Drug Response
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Factors That Can Cause the Individual Variability in Drug Response
Age
Gender
Influence
by unknown
factors ↓
Random effects
Body weight
Possible
Factors ↓
Fixed effects
Liver function
Kidney function
Genotype
Population PK/PD Analysis
by Mixed Effect Model
Combination drugs
Plasma proteins
Race
etc.

7. Population Pharmacokinetics (PK) and Pharmacodynamics (PD)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Population Pharmacokinetics (PK) and Pharmacodynamics (PD)
describe typical profiles of PK/PD in a target population (patients that a drug is applied).
describe magnitudes of inter- and intra-individual variability.
describe factors that can affect the PK/PD of a drug (genetic, physiological, pathological, environmental).
provide dosing guidance for special populations such as geriatrics, pediatrics, organ dysfunction, drug interactions, genetic deficiency of a particular enzyme ... etc.
provide a scientific basis for individualization of dosage regimen.
can be studied based upon sparsely sampled data. → Feasible method to obtain patient data.

8. Feasibility and Outcome
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Drug Concentration Monitoring in Patients: Sparse Sampling by Pharmacokinetic Screen
Single Trough Screen
Plasma Concentration
Time
Multiple Trough Screen
Time
Full Screen
Time
Varying the sampling timing
Once per individual
Multiple trough measurement
Easy &
Less cost
More
informative
Feasibility and Outcome

9. Ph 1: Standard PK sampling
Blood sampling schedule conducted in the clinical trials of Gemcitabine (in U.S. and Japan)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2 2 4 6 8 10 12 14 1 3
Time after starting infusion (hr)
Plasma concentration (mg/ml)
Ph 1: Standard PK sampling
Ph 2b: Pop PK sampling
During infusion
（3～15 min）
3～45 min post infusion
45～90 min post infusion 18 16 14 ● ● 12 10
Plasma concentration (mg/ml) 8
Simulated curve by the Bayesian method 6 4 ● 2
day 1
day 8
day 15

10. Population Pharmacokinetics and Bayesian Estimation Method
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Population Pharmacokinetics and Bayesian Estimation Method
Population
Information
Individual
Feedback

11. PK/PD Relationship of Antibacterial Agents
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
PK/PD Relationship of Antibacterial Agents
Efficacy of Aminoglycosides
Peak
AUC / MIC
Efficacy of New Quinolones
Plasma Concentration
AUC
Trough
MIC
Time above MIC
Safety of Aminoglycosides 4 8 12 16
Time (hr)
Efficacy of b-lactam, macrolides, glycopeptides 20

12. PK/PD Relationship of Grepafloxacin for Clinical Cure
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
PK/PD Relationship of Grepafloxacin for Clinical Cure
3rd Kitasato Harvard Symposium
2002/10/2
110 50 60 70 80 90
100 10
1000
10000
% Probability of Clinical Cure
AUC / MIC
A. Forrest et al. J. Antimicrob. Chemother

13. “New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Bridging Study - ICH E5 -
A supplemental study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data package to the new region. Such studies could include further pharmacokinetic information.
Definition of not only PK but also PD and dose-response early in the development program may facilitate the determination of the need for, and nature of, any requisite bridging data.

14. Complete Clinical Data Package with Bridging: Typical Framework
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Complete Clinical Data Package with Bridging: Typical Framework
Bridging Data Package
New Region
Original Region
PK/PD
Counterparts for the Bridging Study
Bridging Study
Confirmatory Studies
Long-term Studies
Special Populations
Extrapolation of the foreign clinical data

15. First Successful Example: Docetaxel Efficacy/Safety Profiles
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
First Successful Example: Docetaxel
60 mg/m2
100 mg/m2
Clinical Data
Population PK/PD
Population PK/PD
PK/PD
Efficacy/Safety Profiles
©Y.Tanigawara

16. Interpretation of PK Data (1)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Interpretation of PK Data (1)
Clinical PK data in Japanese are essential for the complete clinical data package.
If there is a difference…
Conduct a population PK analysis to gain an insight into the observed ethnic difference.
It might be caused due to different body sizes between Japanese and Caucasian.
It might be caused by different enzymatic activity.
It might be a consequence of different food conditions (low fat, high fat, fasted, non-fasted).
Explainable … ?

17. Use of Population PK to determine factors affecting PK
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Use of Population PK to determine factors affecting PK
Plasma concentration (ng/mL)
Japan (Fed)
US+EU (Fasted)
Difference between Trials
Time (hr) 6 12 18 24 20 40 60
Effect of Food
Time (hr) 6 12 18 24
Plasma concentration (ng/mL) 20 40 60 80
100
Fasted condition
Fed condition
Apparent difference between Japanese and Caucasian resulted from the different food condition.
Tatami et al. ISSX, JSSX 2001.

18. Interpretation of PK Data (2)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Interpretation of PK Data (2)
Clinical PK data in Japanese are essential for the complete clinical data package.
If there is a PK difference…
How much PK difference impacts on clinical efficacy and safety. Need to modify dose?
Require a PK/PD or dose-response relationship to consider the influence of PK difference.
Secondary use of a BE criteria when PK/PD data are absent.

19. Steep PD is Sensitive to PK Difference.
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Steep PD is Sensitive to PK Difference.
Response 3%
30%
30%
30%
Exposure
(PK)

20. Pharmacogenomics Altered PK Altered PD
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Pharmacogenomics
Genetic polymorphisms of drug metabolizing enzymes
Altered PK
Altered PD
Altered Efficacy/Safety profiles
Influences of genotype are attributed to individual variability, rather than racial difference.

21. “New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Difference in Plasma Concentrations of Omeprazole between CYP2C19 Extensive and Poor Metabolizers
1500
Frequency of PM
Caucasian 2～3%
Poor Metabolizer (PM)
Japanese 20%
1000
Plasma concentration (ng/ml)
500
Extensive Metabolizer (EM) 2 4 6 8 10 12
Time after Dose (hr)
Kita et al., Pharm Res 18: 615, 2001

22. “New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
24-hour Intragastric pH Profile Following Morning and Evening Dose of Omeprazole(OPZ)
Intragastric pH
OPZ
OPZ 7 6
OPZ
(20mg twice a day)
CYP2C19 EM 5 4 3
Basal 2 1
Meal intake
Time
9:00
15:00
21:00
3:00
CYP2C19 PM 7 1 2 3 4 5 6
Time
9:00
15:00
21:00
3:00
OPZ
Kita et al., Pharm Res 18: 615, 2001

23. H. pylori Eradication rate (%)
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
CYP2C19 genotype-related efficacy of omeprazole for the eradication of Helicobacter pylori
H. pylori Eradication rate (%)
Metronidazole
+ AMPC
+ Bismuth
+ H2 antagonists
88% (7/8)
83% (5/6)
80% (4/5)
84% (16/19)
100% (1/1)
84% (21/25)
Omeprazole
40% (4/10)
44% (4/9)
33% (1/3)
41% (9/22)
+ AMPC
100% (2/2)
100% (4/4)
50% (13/26)
Omeprazole
+ CAM
75% (15/20)
90% (19/21)
80% (4/5)
83% (38/46)
+ AMPC
100% (5/5)
100% (1/1)
100% (11/11)
86% (49/57)
Regimen
CYP2C19*1/*1
CYP2C19*1/*2
CYP2C19*1/*3 EM
CYP2C19*2/*2
CYP2C19*2/*3
CYP2C19*3/*3 PM
Total
(Tanigawara et al., Clin. Pharmacol. Ther. 66,1999)

24. Summary PK/PD provides a scientific basis for dose range finding.
“New Approaches of Dose Range Finding”
Prof. Y. Tanigawara, Keio University
3rd Kitasato Harvard Symposium
2002/10/2
Summary
PK/PD provides a scientific basis for dose range finding.
Population PK/PD analysis coupled with the sparse blood sampling is an important strategy for drug development.
Pharmacogenomics will be a useful approach for targeting patient population.