Simultaneous/Worldwide Development Strategies : New Challenges

New Approaches of Dose Range Finding

Prof. Yusuke TanigawaraKeio University Hospital

Tokyo, Japan

3rd Kitasato Harvard Symposium2 October 2002

Y.Tanigawara 2002 2

Drug Action

E=f(C(t), S)

> E=f(Dose, S)

Res

pons

e

Concentration (Exposure)

PD data

Time

Con

cent

ratio

n

Dose

PK data

Efficacy

Toxicity

ResponsePlasmaConcen-tration

Siteof

action

Dose&

DosageRegimen

Pharmacokinetics(PK)

Pharmacodynamics(PD)

©Y.Tanigawara

Y.Tanigawara 2002 4

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.

Why PK/PD are needed.

Development Phases and Types of Study (ICH E8)

II III IVI

Phases of Development

Therapeutic Use

TherapeuticConfirmatory

TherapeuticExploratory

HumanPharmacology

PK or PK/PD studyin Patients

Y.Tanigawara 2002 6

Factors That Can Cause the Individual Variability in Drug Response

Age

Gender

Combination drugs

Liver function

Kidney function

Genotype

Body weightPossibleFactors

↓Fixed effects

Influenceby unknown

factors ↓

Random effects

Population PK/PD Analysisby Mixed Effect Model

Plasma proteinsRaceetc.

Y.Tanigawara 2002 7

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.

Y.Tanigawara 2002 8

Full Screen

Time

Multiple Trough Screen

Time

Single Trough Screen

Pla

sma

Con

cent

ratio

n

Time

Drug Concentration Monitoring in Patients: Sparse Sampling by Pharmacokinetic Screen

Once per individual Multiple trough measurement

Varying the sampling timing

Easy &Less cost

More informativeFeasibility and Outcome

9

Blood sampling schedule conducted in the clinical trials of Gemcitabine (in U.S. and Japan)

0

2

4

6

8

10

12

14

16

18

Pla

sma

conc

entr

atio

n (

g/m

l)

day 1 day 8 day 15

● ●

●

Ph 1: Standard PK sampling

Ph 2b: Pop PK sampling0

2

4

6

8

10

12

14

0 1 2 3 4Time after starting infusion (hr)

Pla

sma

conc

entr

atio

n (

g/m

l)

During infusion（ 3～ 15 min） 3 ～ 45 min po

st infusion45 ～ 90 min post infusion

Simulated curve by the Bayesian method

10

Population Pharmacokinetics andBayesian Estimation Method

PopulationInformation

IndividualFeedback

Y.Tanigawara 2002 11

PK/PD Relationship of Antibacterial Agents

0 4 8 12 16 Time (hr)

Pla

sma

Con

cent

ratio

n

AUC

Time above MICMIC

Peak

Trough

AUC / MIC

Efficacy of Aminoglycosides

Safety of Aminoglycosides

Efficacy of New Quinolones

Efficacy of -lactam, macrolides, glycopeptides

Y.Tanigawara 2002 12A. Forrest et al. J. Antimicrob. Chemother. 1997.

% P

roba

bilit

y of

Clin

ical

Cur

e 110

50

60

70

80

90

100

10 100 1000 10000

AUC / MIC

PK/PD Relationship of Grepafloxacinfor Clinical Cure

Y.Tanigawara 2002 13

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.

Y.Tanigawara 2002 14

Complete Clinical Data Package with Bridging:Typical Framework

PK/PD PK/PD

Bridging Data PackageNew Region Original Region

Counterparts for the Bridging StudyBridging Study

Confirmatory Studies

Long-term Studies

Special Populations

Extrapolation of the foreign clinical data

15

First Successful Example: Docetaxel

60 mg/m2 100 mg/m2

Clinical Data

PK/PDEfficacy/Safety Profiles

Population PK/PDPopulation PK/PD

©Y.Tanigawara

Y.Tanigawara 2002 16

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 … ?

Y.Tanigawara 2002 17

Use of Population PK to determine factors affecting PK

Tatami et al. ISSX, JSSX 2001.

Apparent difference between Japanese and Caucasian resulted from the different food condition.

Pla

sma

conc

entr

atio

n (n

g/m

L)

Japan (Fed)

US+EU (Fasted)

Difference between TrialsDifference between Trials

Time (hr)

0 6 12 18 24

0

20

40

60

Effect of FoodEffect of Food

Time (hr)

0 6 12 18 24

Pla

sma

conc

entr

atio

n (n

g/m

L)0

20

40

60

80

100

Fasted condition

Fed condition

Y.Tanigawara 2002 18

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.

Y.Tanigawara 2002 19

Steep PD is Sensitive to PK Difference.

Exposure versus Response Relationship

0

20

40

60

80

100

0 1 2 3 4

Response

Exposure(PK)

30%30%

3%

30%

Y.Tanigawara 2002 20

Pharmacogenomics

Genetic polymorphisms of drug metabolizing enzymes

Influences of genotype are attributed to individual variability, rather than racial difference.

Altered PK

Altered PD

Altered Efficacy/Safety profiles

Y.Tanigawara 2002 21

Extensive Metabolizer (EM)

Difference in Plasma Concentrations of Omeprazole between CYP2C19 Extensive and Poor Metabolizers

Caucasian 2～ 3%Japanese 20%

Frequency of PM1500

0 2 4 6 8 10 12

Pla

sma

conc

entr

atio

n (n

g/m

l)

1000

500

0

Time after Dose (hr)

Poor Metabolizer (PM)

Kita et al., Pharm Res 18: 615, 2001

22

24-hour Intragastric pH Profile Following Morning and Evening Dose of Omeprazole(OPZ)

CYP2C19

EM

7

123456

OPZOPZ

CYP2C19

PM

7

123456

Time 9:00 15:00 21:00 3:00 9:00

OPZ OPZ

Kita et al., Pharm Res 18: 615, 2001

OPZ(20mg twice a day)

Basal

Meal intake

Intragastric pH

Time 9:00 15:00 21:00 3:00 9:00

(Tanigawara et al., Clin. Pharmacol. Ther. 66,1999)

H. pylori Eradication rate (%)

Regimen

CYP2C19*1/*1

Metronidazole

+ AMPC+ Bismuth

+ H2 antagonists

88% (7/8)83% (5/6)80% (4/5)

84% (16/19)

100% (1/1)80% (4/5)

83% (5/6)84% (21/25)

EM

PMTotal

CYP2C19*1/*2CYP2C19*1/*3

CYP2C19*2/*2CYP2C19*2/*3CYP2C19*3/*3

Omeprazole

40% (4/10)44% (4/9)33% (1/3)

41% (9/22)

+ AMPC

100% (2/2)100% (2/2)

100% (4/4)50% (13/26)

CYP2C19 genotype-related efficacy of omeprazole for the eradication of Helicobacter pylori

Omeprazole

+ CAM

75% (15/20)90% (19/21)80% (4/5)83% (38/46)

+ AMPC

100% (5/5)100% (5/5)100% (1/1)

100% (11/11)86% (49/57)

Y.Tanigawara 2002 24

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.