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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

2 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 2 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

3 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 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 DOSECONCENTRATIONRESPONSE PKPD DISEASE PROGRESSION

4 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 4 Drug Development = Continuum for Model Development & Application Phase IIbPhase III Learn MTD Human PKPD Learn Efficacy Dose-response Exposure-response Dose Adjustments Confirm Therapeutic Benefit Covariate effects Phase I Phase IIa Preclinical Learn Efficacy Tox E-R Labelling and post- marketing efforts PK/PD Mechanistic PK/PD……..(pop)PK/PD……………………….pop PK/PD Biomarker/Surrogate………………………..Clinical endpoint UNCERTAINTY diminished with increased knowledge and understanding

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

6 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 6 Multiple Ascending Dose Study How evident is exposure-response (PK- PD) relationship based on an early marker in healthy subjects? Phase 1

7 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 7 Multiple Ascending Dose Study PK-PD relationship evident & quantifiable (nonlinear Emax model) Investigated doses = concentrations within apparent efficacious range 0 1 2 3 4 7654321076543210 O Placebo O Dose 1 O Dose 2 O Dose 3 --- Model Prediction Phase 1 Concentration Marker

8 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 8 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

9 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 9 PK-PD Study – Surrogate Marker I Phase 1 0 1 2 3 4 5 Drug X (red) was more potent than Comparator Y (blue) Relative potencies (EC 50 of X vs. Y) very consistent across multiple response variables

10 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 10 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 Marker II

11 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 11 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

12 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 12 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

13 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 13 Dose-Response for Comparator Y: Response I 0 1 2 3 4 0123401234 Literature data (o) Mean Prediction ( ___ ) Uncertainty range: based on 95% CIs of parameter estimates Phase 1 Phase 2a

14 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 14 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 EC 50 of Drug X vs. Comparator Y –Accounted for PK differences –Additional variability for uncertainty in scaling ratios Phase 1 Phase 2a

15 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 15 Select doses to further characterize (reduce uncertainty in) response surface Target doses ~ 50% (ED 50 ), 80% (ED 80 ) & max effects (E max ) Scaled Dose-Response for Drug X: Response I Phase 1 Phase 2a 0123401234 0 1 2 3 4

16 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 16 Phase 2a Study: Response I Observed results for Drug X (o) provided the desired response range Phase 2a 0123401234 0 1 2 3 4

17 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 17 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

18 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 18 PK-PD for Response I i.e. – if Target Response Target Cmax Phase 2a Response I Dose Cmax (concentration) Drug X

19 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 19 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 Marker II

20 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 20 Simulated Mean Concentration vs. Time hgfedcba0 6 5 4 3 2 1 0 TIME Concentration 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

21 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 21 hgfedcba0 6 5 4 3 2 1 0 TIME Concentration 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

22 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 22 0abcdefgh Time Concentration Simulated Individuals Mean 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

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

24 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC September 29, 2006 24 Questions? metrum research group LLC 2 Tunxis Rd, Suite 112 Tariffville, CT 06081 Tel: 860.670.0744 Fax: 860.760.6014 www.metrumrg.com


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