ExposureResponse PKPD Applied to ModelBased Drug Development A
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 1 FDA/Industry Workshop: Case Studies in M&S 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 2 a Phase 2 b Phase 2 Phase 3 2 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
…the science of interpreting and describing pharmacology in a quantitative fashion (e. g. through modeling and simulation) DOSE CONCENTRATION PK • • DISEASE PROGRESSION Pharmacometrics RESPONSE PD Determine typical population response Understand quantify variability in PK and response 3 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Drug Development = Continuum for Model Development & Application Preclinical Learn Efficacy Tox E-R Phase IIa Phase IIb Learn MTD Efficacy Dose-response Human PKPD Exposure-response Dose Adjustments PK/PD Mechanistic Phase III Labelling and postmarketing efforts Confirm Therapeutic Benefit Covariate effects 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 4 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 2 a) Clinical Response I & II (Phase 2 b) • Guide / support dose & formulation selection with input into trial design – Phase 1 Phase 2 a – Phase 2 a Phase 2 b – Phase 2 Phase 3 5 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 Multiple Ascending Dose Study • How evident is exposure-response (PKPD) relationship based on an early marker in healthy subjects? 6 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 Multiple Ascending Dose Study • • PK-PD relationship evident & quantifiable (nonlinear ‘Emax’ model) Investigated doses = concentrations within apparent efficacious range 7 O O --- 6 Marker 5 Placebo Dose 1 Dose 2 Dose 3 Model Prediction 4 3 2 1 0 0 1 2 3 Concentration FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC 4 7
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 2 a – Determine dose of X ~ comparable to comparator dose of Y using PK and PK-PD differences – Support selection of dose range for Phase 2 a study 8 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 PK-PD Study – Surrogate Marker I Drug X (red) was more potent than Comparator Y (blue) Relative potencies (EC 50 of X vs. Y) very consistent across multiple response variables 0 1 2 3 4 5 • • 9 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
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 “effect” Marker II Concentration range associated with “no effect” Concentration FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC 10
Phase 1 PK-PD Study • Drug X ‘worked’, but… what dose(s) should go into Phase 2 a? – Obvious Choice: Dose of X ~ Comparator Y Dose – But… what +/- multiple(s) of Dose X? • Phase 2 a: Primary endpoint = clinical outcome measure (Response I) 11 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 PK-PD Study • Drug X ‘worked’, but what doses should go into Phase 2 a, 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 12 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 Phase 2 a Dose-Response for Comparator Y: Response I 0 1 Literature data (o) 2 Uncertainty range: based on 95% CI’s of parameter estimates 3 Mean Prediction (___) 4 0 1 2 3 4 13 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 Phase 2 a PK-PD Study • Drug X ‘worked’, but what doses should go into Phase 2 a, 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 14 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 1 Phase 2 a Scaled Dose-Response for Drug X: Response I • Select doses to further characterize (reduce uncertainty in) response surface 0 1 2 3 4 • Target doses ~ 50% (ED 50), 80% (ED 80) & max effects (Emax) 15 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 2 a Study: Response I • Observed results for Drug X (o) provided the desired response range 0 1 2 3 4 16 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 2 a 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 2 b – 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 17 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 2 a PK-PD for Response I Dose Response I i. e. – if Target Response Target Cmax (concentration) Drug X 18 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Phase 2 a PK-PD for Surrogate Marker II • PK-PD relationship very consistent with Phase 1 prediction “Effect” range “No effect” range O Marker II __ Drug X Observed (Phase 2) Predicted (Phase 1) Concentration FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC 19
Phase 2 a 2 b Simulated Mean Concentration vs. Time • With this PK profile, dose provides for Response I but may 6 not for Response II From Phase 2 a Modeling Concentration 5 To get from Phase 2 b Modeling 4 3 PK-PD not quantified yet = considerable uncertainty in target concentration range Response I 2 Response II 1 0 0 a FDA/Industry Workshop: Case Studies in M&S b c d TIME Copyright 2006, metrum research group e LLC f g 20 h
Phase 2 a 2 b Example: Simulated “Modified” Mean PK Time Profile 6 • Composite of PK & PK-PD Modeling to direct & support dose & formulation choices Concentration 5 4 3 Response II 2 1 0 0 a b c d TIME FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC e f g 21 h
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 Concentration Simulated Individuals Mean Prediction 0 FDA/Industry Workshop: Case Studies in M&S a b c d Time e Copyright 2006, metrum f g h 22 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 23 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
Questions? metrum research group LLC 2 Tunxis Rd, Suite 112 Tariffville, CT 06081 Tel: 860. 670. 0744 Fax: 860. 760. 6014 www. metrumrg. com 24 FDA/Industry Workshop: Case Studies in M&S Copyright 2006, metrum research group LLC
- Slides: 24