office of clinical pharmacology and biopharmaceutics idsa/isap/fda workshop 4/16/04 1 improvement in...

1Office of Clinical Pharmacology and BiopharmaceuticsOffice of Clinical Pharmacology and BiopharmaceuticsIDSA/ISAP/FDA Workshop 4/16/04IDSA/ISAP/FDA Workshop 4/16/04

Improvement in Dose Selection: Improvement in Dose Selection: FDA PerspectiveFDA Perspective

Improvement in Dose Selection: Improvement in Dose Selection: FDA PerspectiveFDA Perspective

IDSA/ISAP/FDA WorkshopApril 16, 2004

Jenny J Zheng, Ph.D.Pharmacometrician

DPEIII/OCPB/CDER/FDA

IDSA/ISAP/FDA WorkshopApril 16, 2004

Jenny J Zheng, Ph.D.Pharmacometrician

DPEIII/OCPB/CDER/FDA


ObjectivesObjectivesObjectivesObjectives

• To discuss the studies to support dose selection

• To discuss a model based quantitative approach to guide dose selection

• To discuss approaches to further advance the use of PK/PD for dose selection

• To discuss the studies to support dose selection

• To discuss a model based quantitative approach to guide dose selection

• To discuss approaches to further advance the use of PK/PD for dose selection


Dose SelectionDose SelectionDose SelectionDose Selection

• Efficacy

• Safety

• Efficacy

• Safety

• Resistance


Studies to Support Dose SelectionStudies to Support Dose SelectionStudies to Support Dose SelectionStudies to Support Dose Selection1. Microbiology / in vitro data

• Susceptibility data for pathogens relevant to the indication

• Protein binding• Post antibiotic effect (PAE)

2. Pre-clinical data• PK/PD studies in various animal/in vitro

models• Efficacy studies in various therapeutic

infection models • PK studies in the animals used in

therapeutic infection models

1. Microbiology / in vitro data• Susceptibility data for pathogens relevant

to the indication• Protein binding• Post antibiotic effect (PAE)

2. Pre-clinical data• PK/PD studies in various animal/in vitro

models• Efficacy studies in various therapeutic

infection models • PK studies in the animals used in

therapeutic infection models


Studies to Support the Dose SelectionStudies to Support the Dose SelectionStudies to Support the Dose SelectionStudies to Support the Dose Selection

3. Phase 1 pharmacokinetic studies• PK studies in healthy subjects

4. Phase 2 studies• Efficacy• Safety

3. Phase 1 pharmacokinetic studies• PK studies in healthy subjects

4. Phase 2 studies• Efficacy• Safety


Time to Communicate with FDATime to Communicate with FDATime to Communicate with FDATime to Communicate with FDA

• Early communication is encouraged.

• Prior to phase 2/3 studies

• Early communication is encouraged.

• Prior to phase 2/3 studies


How to Select DoseHow to Select DoseHow to Select DoseHow to Select Dose

• Rationale for dose selection in antimicrobial drug applications is variable.

• Very often the dose is selected based on mean PK profile in relation to MIC for relevant pathogens.– The PK variability of drug is not considered. – The relationship between a concentration-

time profile and a MIC is not always clear.

• A quantitative approach is recommended.

• Rationale for dose selection in antimicrobial drug applications is variable.

• Very often the dose is selected based on mean PK profile in relation to MIC for relevant pathogens.– The PK variability of drug is not considered. – The relationship between a concentration-

time profile and a MIC is not always clear.

• A quantitative approach is recommended.


Quantitative ApproachQuantitative ApproachQuantitative ApproachQuantitative Approach

• What is quantitative approach?– Use modeling and simulation tools to

quantitatively predict the outcome.

• Advantage of quantitative approach– Quantitative (predictive)– Decision is more logical and transparent– Objective

• What is quantitative approach?– Use modeling and simulation tools to

quantitatively predict the outcome.

• Advantage of quantitative approach– Quantitative (predictive)– Decision is more logical and transparent– Objective


Quantitative ApproachQuantitative ApproachQuantitative ApproachQuantitative Approach

Dose X

Time in hour

Co

nce

ntr

atio

n in

ug

/mL

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Pathogen

• Can pathogen be killed at dose X?

• A PK/PD index can be obtained from pre-clinical studies and be used to predict the bacterial killing/inhibition effect .

• If the PK/PD index for the unbound drug in the subject is above the PK\PD index obtained from pre-clinic: YES.Otherwise: NO

PKProtein binding


The GoalThe GoalThe GoalThe Goal• To predict the percentage of patients who could

reach a PK/PD target at a range of doses.

• Dose/doses can be determined for clinical trials:– Phase 3 (fixed dose): majority of subjects would

reach the PK/PD target.

– Phase 2 dose ranging studies: the doses should be selected so that it is differentiable with regard the percent of subjects who could reach the PK/PD target among the doses.

• To predict the percentage of patients who could reach a PK/PD target at a range of doses.

• Dose/doses can be determined for clinical trials:– Phase 3 (fixed dose): majority of subjects would

reach the PK/PD target.

– Phase 2 dose ranging studies: the doses should be selected so that it is differentiable with regard the percent of subjects who could reach the PK/PD target among the doses.


The MethodThe MethodThe MethodThe Method• PK data PK model (parameters and its variability) PK profiles at doses even not studied.• PK data PK model (parameters and its variability) PK profiles at doses even not studied.

Time in hour

Co

nce

ntr

atio

n in

ug

/mL

0 10 20 30

0.0

0.5

1.0

1.5

2.0

2.5

3.0


The MethodThe MethodThe MethodThe Method• Distribution of PK/PD index at dose X• Distribution of PK/PD index at dose X

AUC/MIC when MIC=0.5ug/mL

Fre

quen

cy

20 40 60 80 100

05

1015

2025

AUC/MIC when MIC=0.5ug/mL

Fre

quen

cy

20 40 60 80 100

05

1015

2025

77%


The MethodThe MethodThe MethodThe Method

The multiple of dose

% o

f su

bjec

t w

ith A

UC

/MIC

>35

0 2 4 6 8 10

020

4060

8010

0

The multiple of dose

% o

f su

bjec

t w

ith A

UC

/MIC

>35

0 2 4 6 8 10

020

4060

8010

0

MIC90=0.5 g/mL

MIC90=1 g/mL

MIC90=2 g/mL

X1

X2

X3X4


Antimicrobial Model Antimicrobial Model Antimicrobial Model Antimicrobial Model • Successful treatment of infection involves the

interactions of host, drug and bacteria• Successful treatment of infection involves the

interactions of host, drug and bacteria

Host Drug

Bacteria s

PharmacokineticsTissue penetration

• Susceptibility of pathogens• PK/PD relationship

• PAE• Killing rate• Other metrics

Immune system

?

??

?

• The factors not being considered may represent potential limitations.


PK/PD Studies in HumanPK/PD Studies in HumanPK/PD Studies in HumanPK/PD Studies in Human

• The predictability of PK/PD relationship

in animals for treatment of infections in

human is not clear.

• The PK/PD relationship for most of drugs

was established only in animals.

• To improve understanding the PK/PD

relationship in human:

– Phase 2/3 studies

• The predictability of PK/PD relationship

in animals for treatment of infections in

human is not clear.

• The PK/PD relationship for most of drugs

was established only in animals.

• To improve understanding the PK/PD

relationship in human:

– Phase 2/3 studies


SummarySummarySummarySummary

• A model based quantitative approach is

informative for dose selection.• With the potential limitations, the dose should

be selected based on the totality of available data.

• Dose selection:

• A model based quantitative approach is

informative for dose selection.• With the potential limitations, the dose should

be selected based on the totality of available data.

• Dose selection:

MicrobiologyPre-clinic Phase 1 Phase 3Phase 2


FutureFutureFutureFuture• Well designed dose ranging phase 2

studies in appropriate infections.– PK/PD relationship in human– Safety

• Improvement of the model used in quantitative approach.– Efficacy + Safety + Resistance

• Evaluation of indices other than AUC/MIC, Cmax/MIC, and T>MIC.

• Development of optimal duration of therapy.

• Well designed dose ranging phase 2 studies in appropriate infections.– PK/PD relationship in human– Safety

• Improvement of the model used in quantitative approach.– Efficacy + Safety + Resistance

• Evaluation of indices other than AUC/MIC, Cmax/MIC, and T>MIC.

• Development of optimal duration of therapy.

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