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

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

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

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

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

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

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 1 O Dose 2 O Dose 3 --- Model Prediction 0 1 2 3 4 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC

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

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

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

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

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

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 (___) 0 1 2 3 4 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC

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

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 0 1 2 3 4 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC

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

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

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

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

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

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

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

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

Questions? metrum research group LLC www.metrumrg.com 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