Transcript New Approaches of Dose Range Finding

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
Drug Action
E=f(C(t), S)
> E=f(Dose, S)
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Pharmacokinetics
(PK)
Dose
&
Dosage
Regimen
Plasma
Concentration
Pharmacodynamics
(PD)
Site
of
action
©Y.Tanigawara
PD data
Response
Concentration
PK data
Response
Dose
Efficacy
Toxicity
Time
Concentration (Exposure)
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.
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Development Phases and Types of Study (ICH E8)
Therapeutic Use
Therapeutic
Confirmatory
PK or PK/PD study
in Patients
Therapeutic
Exploratory
Human
Pharmacology
I
II
III
Phases of Development
IV
Factors That Can Cause the Individual Variability
in Drug Response
Age
Gender
Possible
Factors
↓
Fixed
effects
Body weight
Liver function
Kidney function
Genotype
Combination drugs
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Influence
by unknown
factors
↓
Random
effects
Plasma proteins
Race
etc.
Population PK/PD Analysis
by Mixed Effect Model
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Population Pharmacokinetics (PK) and
Pharmacodynamics (PD)
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




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.
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Drug Concentration Monitoring in Patients:
Sparse Sampling by Pharmacokinetic Screen
Full Screen
Plasma Concentration
Single Trough Screen Multiple Trough Screen
Time
Once per individual
Easy &
Less cost
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Time
Multiple trough
measurement
Feasibility and Outcome
Time
Varying the
sampling timing
More
informative
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Blood sampling schedule conducted in the clinical trials
of Gemcitabine (in U.S. and Japan)
Plasma concentration (mg/ml)
14
Ph 1: Standard PK sampling
12
10
8
6
4
2
0
0
Plasma concentration (mg/ml)
18
During infusion
（3～15 min）
16
14
12
1
2
3
Time after starting infusion (hr)
●
4
Ph 2b: Pop PK sampling
3～45 min post
infusion
45～90 min post
infusion
●
10
8
6
4
●
2
0
day 1
day 8
day 15
Simulated
curve by the
Bayesian
method
Population Pharmacokinetics and
Bayesian Estimation Method
Population
Information
Individual
Feedback
PK/PD Relationship of Antibacterial Agents
Plasma Concentration
Efficacy of Aminoglycosides
Peak
AUC / MIC
AUC
Efficacy of New Quinolones
Trough
MIC
Time above MIC
0
4
8
Safety of Aminoglycosides
12
16
Time (hr)
Efficacy of b-lactam, macrolides, glycopeptides
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% Probability of Clinical Cure
PK/PD Relationship of Grepafloxacin
for Clinical Cure
110
100
90
80
70
60
50
10
100
1000
10000
AUC / MIC
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A. Forrest et al. J. Antimicrob. Chemother. 1997.
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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 doseresponse early in the development program may
facilitate the determination of the need for, and
nature of, any requisite bridging data.
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Complete Clinical Data Package with Bridging:
Typical Framework
New Region
Bridging Data Package
Original Region
PK/PD
PK/PD
Bridging Study
Counterparts for
the Bridging Study
Confirmatory Studies
Extrapolation of the
foreign clinical data
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Long-term Studies
Special Populations
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First Successful Example: Docetaxel
60 mg/m2
Population PK/PD
100 mg/m2
Clinical Data
Population PK/PD
PK/PD
Efficacy/Safety Profiles
©Y.Tanigawara
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 … ?
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Use of Population PK to determine factors affecting PK
Effect of Food
Plasma concentration (ng/mL)
Plasma concentration (ng/mL)
Difference between Trials
60
100
US+EU (Fasted)
40
20
Japan (Fed)
0
0
6
12
Time (hr)
18
24
80
Fasted condition
60
40
20
Fed condition
0
0
6
12
18
24
Time (hr)
Apparent difference between Japanese and Caucasian resulted
from the different food condition.
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Tatami et al. ISSX, JSSX 2001.
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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.
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Steep PD is Sensitive to PK Difference.
Response
3%
30%
Exposure versus Response Relationship
100
80
60
40
20
30%
30%
0
0
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1
2
3
4
Exposure
(PK)
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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.
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Plasma concentration (ng/ml)
Difference in Plasma Concentrations of Omeprazole
between CYP2C19 Extensive and Poor Metabolizers
1500
Frequency of PM
Caucasian 2～3%
Japanese
20%
1000
Poor Metabolizer (PM)
500
Extensive Metabolizer (EM)
0
0
2
4
6
8
10
12
Time after Dose (hr)
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Kita et al., Pharm Res 18: 615, 2001
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24-hour Intragastric pH Profile Following Morning and
Evening Dose of Omeprazole(OPZ)
Intragastric pH OPZ
CYP2C19
EM
OPZ
7
6
5
4
3
2
1
OPZ
(20mg twice a day)
Basal
Meal intake
9:00
15:00
OPZ
CYP2C19
PM
21:00
3:00
9:00 Time
OPZ
7
6
5
4
3
2
1
Kita et al., Pharm Res 18: 615, 2001
9:00
15:00
21:00
3:00
9:00 Time
CYP2C19 genotype-related efficacy of omeprazole
for the eradication of Helicobacter pylori
H. pylori Eradication rate (%)
Metronidazole
+ AMPC
+ Bismuth
+ H2 antagonists
Omeprazole
+ AMPC
Omeprazole
+ AMPC
+ CAM
CYP2C19*1/*1
CYP2C19*1/*2
CYP2C19*1/*3
EM
88% (7/8)
83% (5/6)
80% (4/5)
84% (16/19)
40% (4/10)
44% (4/9)
33% (1/3)
41% (9/22)
75% (15/20)
90% (19/21)
80% (4/5)
83% (38/46)
CYP2C19*2/*2
CYP2C19*2/*3
CYP2C19*3/*3
PM
Total
100% (1/1)
80% (4/5)
100% (2/2)
100% (2/2)
83% (5/6)
84% (21/25)
100% (4/4)
50% (13/26)
100% (5/5)
100% (5/5)
100% (1/1)
100% (11/11)
86% (49/57)
Regimen
(Tanigawara et al., Clin. Pharmacol. Ther. 66,1999)
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.
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