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

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

3. Copyright 2006, metrum research group LLC
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
PROGRESSION
DISEASE
DOSE
CONCENTRATION
RESPONSE PK PD
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

4. Drug Development = Continuum for Model Development & Application
Phase I
Phase IIa
Preclinical
Phase IIb
Phase III
Labelling and post-marketing efforts
Learn
Efficacy
Tox
E-R
Learn
MTD
Human PKPD
Learn
Efficacy Dose-response
Exposure-response
Dose Adjustments
Confirm
Therapeutic
Benefit
Covariate effects
PK/PD Mechanistic
PK/PD……..(pop)PK/PD……………………….pop PK/PD Biomarker/Surrogate………………………..Clinical endpoint
UNCERTAINTY diminished with increased knowledge and understanding
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

5. 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
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

6. Multiple Ascending Dose Study
Phase 1
Multiple Ascending Dose Study
How evident is exposure-response (PK-PD) relationship based on an early marker in healthy subjects?
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

7. Multiple Ascending Dose Study
Phase 1
Multiple Ascending Dose Study
PK-PD relationship evident & quantifiable (nonlinear ‘Emax’ model)
Investigated doses = concentrations within apparent efficacious range
Concentration
Marker 7 6 5 4 3 2 1
O Placebo O Dose O Dose O Dose Model Prediction
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

8. Copyright 2006, metrum research group LLC
Phase 1
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
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

9. PK-PD Study – Surrogate Marker I
Phase 1
PK-PD Study – Surrogate Marker I
Drug X (red) was more potent than Comparator Y (blue)
Relative potencies (EC50 of X vs. Y) very consistent across multiple response variables 5 4 3 2 1
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

10. PK-PD Study – Surrogate Marker (SM) II
Phase 1
PK-PD Study – Surrogate Marker (SM) II
Identified Drug X concentrations associated with SM II effect
Consider doses that provide for target concentrations
Concentration range associated with “no effect”
Concentration range associated with “effect”
Marker II
Concentration
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

11. Copyright 2006, metrum research group LLC
Phase 1
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)
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

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

13. Dose-Response for Comparator Y: Response I
Phase 1  Phase 2a
Dose-Response for Comparator Y: Response I 1 2 3 4
Literature data (o)
Uncertainty range: based on 95% CI’s of parameter estimates
Mean Prediction (___)
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

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

15. Scaled Dose-Response for Drug X: Response I
Phase 1  Phase 2a
Scaled Dose-Response for Drug X: Response I
Select doses to further characterize (reduce uncertainty in) response surface
Target doses ~ 50% (ED50), 80% (ED80) & max effects (Emax) 1 2 3 4
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

16. Phase 2a Study: Response I
Observed results for Drug X (o) provided the desired response range 1 2 3 4
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

17. Copyright 2006, metrum research group LLC
Phase 2a
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
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

18. Copyright 2006, metrum research group LLC
Phase 2a
PK-PD for Response I
i.e. – if Target Response
Response I
Dose
Cmax (concentration)
Drug X
Target Cmax
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

19. PK-PD for Surrogate Marker II
Phase 2a
PK-PD for Surrogate Marker II
PK-PD relationship very consistent with Phase 1 prediction
“No effect” range
“Effect” range
Drug X O Observed (Phase 2) __ Predicted (Phase 1)
Marker II
Concentration
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

20. Simulated Mean Concentration vs. Time
Phase 2a  2b
Simulated Mean Concentration vs. Time
With this PK profile, dose provides for Response I but may not for Response II h g f e d c b a 6 5 4 3 2 1
TIME
Concentration
From Phase 2a Modeling
To get from Phase 2b Modeling
PK-PD not quantified yet = considerable uncertainty in target concentration range
Response I
Response II
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

21. Example: Simulated “Modified” Mean PK Time Profile
Phase 2a  2b
Example: Simulated “Modified” Mean PK Time Profile h g f e d c b a 6 5 4 3 2 1
TIME
Concentration
Composite of PK & PK-PD Modeling to direct & support dose & formulation choices
Response I
Response II
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

22. Monte Carlo Simulation
Phase 2  3
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
Simulated Individuals
Mean Prediction
Concentration a b c d e f g h
Time
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

23. 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
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC

24. Questions? metrum research group LLC www.metrumrg.com
2 Tunxis Rd, Suite 112 Tariffville, CT 06081
Tel: Fax:
FDA/Industry Workshop: Case Studies in M&S
Copyright 2006, metrum research group LLC