FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29,...

FDA/Industry Workshop: Case Studies in M&S

Copyright 2006, metrum research group LLC

September 29, 2006 1

Exposure-Response (PK-PD) Applied to Model-Based Drug

Development: A Case Study of Drug X

Matthew M. Riggs, Ph.D.

metrum research group LLC

2 Tunxis Rd, Suite 112 Tariffville, CT 06081

Tel: 860.670.0744 Fax: 860.760.6014

www.metrumrg.com




Overview• Introduction

– PK-PD Modeling & Simulation (M&S) a.k.a. “Pharmacometrics”

– The M&S continuum through drug development

• Example: M&S Continuum Applied to Drug X

– Phase 1 Phase 2a– Phase 2a Phase 2b– Phase 2 Phase 3




Pharmacometrics…the science of interpreting and describing pharmacology in a quantitative fashion (e.g. through modeling and simulation)

• Determine typical population response• Understand and quantify variability in PK

and response

DOSE CONCENTRATION RESPONSE

PK PD

DIS

EA

SE

PR

OG

RE

SS

ION




Drug Development = Continuum for Model Development & Application

Phase IIb Phase III

LearnMTDHuman PKPD

LearnEfficacy Dose-responseExposure-responseDose Adjustments

ConfirmTherapeuticBenefitCovariate effects

Phase I Phase IIaPreclinical

LearnEfficacyToxE-R

Labelling and post-marketing efforts

PK/PDMechanistic

PK/PD……..(pop)PK/PD……………………….pop PK/PD Biomarker/Surrogate………………………..Clinical endpoint

UNCERTAINTY diminished with increased

knowledge and understanding




Drug X: Optimize Therapeutic Profile using M&S Continuum

• How evident is E-R (early Phase 1)?• Quantify therapeutic profile:

– Surrogate Markers (SM) I & II: (Phase 1)– Dose-Response of Comparator– Clinical Response I & SM II (Phase 2a)– Clinical Response I & II (Phase 2b)

• Guide / support dose & formulation selection with input into trial design – Phase 1 Phase 2a– Phase 2a Phase 2b– Phase 2 Phase 3




Multiple Ascending Dose Study

• How evident is exposure-response (PK-PD) relationship based on an early marker in healthy subjects?

Phase 1




Multiple Ascending Dose Study • PK-PD relationship evident & quantifiable (nonlinear ‘Emax’

model) • Investigated doses = concentrations within apparent

efficacious range

0 1 2 3 4

7

6

5

4

3

2

1

0

O Placebo O Dose 1 O Dose 2 O Dose 3 --- Model Prediction

ConcEC

ConcEE

50

max0

*Marker

Phase 1

Concentration

Mar

ker




PK-PD Study • Quantify exposure-response relationship

based on expanded markers in healthy subjects, with active comparator (Y)?– Consider relative PK differences– Compare PK-PD differences (e.g., Surrogate Marker

I)– Begin to define target concentrations for effects

(e.g., Surrogate Marker II)

• Modeling Goal: Support decisions for Phase 2a– Determine dose of X ~ comparable to comparator

dose of Y using PK and PK-PD differences– Support selection of dose range for Phase 2a study

Phase 1




PK-PD Study – Surrogate Marker I

Phase 1

Drug X (red),Comparator Y (blue)

Median Concentration

Me

dia

n R

esp

on

se

EC50 = dashed lines

Median observation at each collection time for each treatment (circles)

PK-PD Model Prediction (solid line)

)(50

)(*)(

)(50

)(*)(Response 0max0max

0YY

Y

XX

X

ConcEC

ConcRE

ConcEC

ConcRER

01

23

45

• Drug X (red) was more potent than Comparator Y (blue)

• Relative potencies (EC50 of X vs. Y) very consistent across multiple response variables




PK-PD Study – Surrogate Marker (SM) II

• Identified Drug X concentrations associated with SM II effect

• Consider doses that provide for target concentrations

Phase 1

Concentration range associated with “no effect”

Concentration range associated with “effect”

Concentration

Mar

ker

II




PK-PD Study

• Drug X ‘worked’, but… what dose(s) should go into Phase 2a?– Obvious Choice: Dose of X ~ Comparator Y

Dose – But… what +/- multiple(s) of Dose X?

• Phase 2a: Primary endpoint = clinical outcome measure (Response I)

Phase 1




PK-PD Study

• Drug X ‘worked’, but what doses should go into Phase 2a, where primary endpoint will be a clinical outcome measure?

• Comparator Y Dose-Response for Response I – Literature data– Model = Nonlinear ‘Emax’ model for mean

relationship– Uncertainty range: Based on standard errors of

parameter estimates

Phase 1




Dose Y

Re

spo

nse

Dose-Response for Comparator Y: Response I

0 1 2 3 4

0

1

2

3

4

Literature data (o)

Mean Prediction (___)

Uncertainty range:

based on 95% CI’s of parameter estimates

Phase 1 Phase 2a




PK-PD Study

• Drug X ‘worked’, but what doses should go into Phase 2a, where primary endpoint will be a clinical outcome measure?

• Comparator Y Dose-Response for Response I • Scaled for Approximate Dose-Response of

Dose X– Based on relative EC50 of Drug X vs. Comparator Y

– Accounted for PK differences– Additional variability for uncertainty in scaling ratios

Phase 1 Phase 2a




• Select doses to further characterize (reduce uncertainty in) response surface

• Target doses ~ 50% (ED50), 80% (ED80) & max effects (Emax)

Dose X

Re

spo

nse

Scaled Dose-Response for Drug X: Response I

Phase 1 Phase 2a

0

1

2

3

40 1 2 3 4




Phase 2a Study: Response I

• Observed results for Drug X (o) provided the desired response range

Phase 2a

Dose X

Re

spo

nse

0

1

2

3

4

0 1 2 3 4




Phase 2 M&S Plan

• Response I– Describe exposure-response using Cmax– Determine Cmax target to provide appropriate

response range

• Response II– To be studied in Phase 2b– Prolonged exposure may be required?– Determine what doses / concentrations

required for Response II

• Consider formulation modifications to prolong exposure, if needed, while retaining Response I target Cmax

Phase 2a




PK-PD for Response I

i.e. – if Target Response

Target Cmax

Phase 2a

Res

pons

e I

Dos

e

Cmax (concentration)Drug X




PK-PD for Surrogate Marker II• PK-PD relationship very consistent with Phase 1 prediction

Phase 2a

Drug X O Observed (Phase 2) __ Predicted (Phase 1)

“No effect” range “Effect” range

Concentration

Mar

ker

II




Simulated Mean Concentration vs. Time

hgfedcba0

6

5

4

3

2

1

0

TIME

Co

nce

ntr

ati

on

Response II

Response I

From Phase 2a Modeling

To get from Phase 2b Modeling

Phase 2a 2b

• With this PK profile, dose provides for Response I but may not for Response II

PK-PD not quantified yet = considerable uncertainty in target concentration range




hgfedcba0

6

5

4

3

2

1

0

TIME

Co

nce

ntr

ati

on

Example: Simulated “Modified” Mean PK Time Profile

Phase 2a 2b

Response I

• Composite of PK & PK-PD Modeling to direct & support dose & formulation choices

Response II




0 a b c d e f g hTime

Co

nce

ntr

ati

on

Simulated IndividualsMean Prediction

Monte Carlo Simulation• Mixed effects model allows for:

– Simulation of expected PK & PK-PD variability– Calculation of % subjects reaching each target

concentration and Response

• Optimize dose & formulation, and trial design, based on relative balance of % of subjects to each target (may include efficacy and safety markers) rather than just attainment of mean

Phase 2 3




Summary – M&S Continuum

• M&S can, does, and should contribute to all phases of development

• PK and PK-PD modeling have supported Drug X clinical development – Real time analyses– Quantitative support for decisions based on

current knowledge & uncertainty – Guided exploration of informative dose

ranges and narrowing appropriate candidate formulations.

• M&S to be continued as development program of Drug X progresses




Questions?metrum research group LLC

2 Tunxis Rd, Suite 112 Tariffville, CT 06081

Tel: 860.670.0744 Fax: 860.760.6014

www.metrumrg.com

FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29,...

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Transcript of FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29,...