PK-PD Modeling and Dosage Determination for Proof-of-Concept Trials - Marc R. Gastonguay, Ph.D. ()

 
PK-PD Modeling and Dosage Determination for Proof-of-Concept Trials - Marc R. Gastonguay, Ph.D. ()
IMMPACT-VIII
                        Early Clinical Study Designs, Emphasizing Proof-of-Concept Trials
                        June 12-14, 2008
                        Arlington, VA

                        PK-PD Modeling and Dosage
                        Determination for Proof-of-Concept Trials

                        Marc R. Gastonguay, Ph.D.
                        (marcg@metrumrg.com)

©2008 metrum research group LLC
PK-PD Modeling and Dosage Determination for Proof-of-Concept Trials - Marc R. Gastonguay, Ph.D. ()
PKPD in Proof of Concept Trials: IMMPACT 2008

                                         Overview
        - PK/PD (Exposure-Response) and Model-Based Drug
          Development

        - Role of Exposure-Response Modeling in Proof-of-Concept
          Trials
                Planning and Design
                Analysis and Quantitative Support for PoC Determination
                Building Knowledge for Later Stage Development
                Other examples of E-R utility

        - Summary Points

©2008 metrum research group LLC                                                                      2
PKPD in Proof of Concept Trials: IMMPACT 2008

        Innovation: Planes are modeled long before takeoff
                NASA Aerospace Engineering Grid
                                                          Wing Models

                                                                                  •Lift Capabilities
                                                                                                                           Stabilizer Models
                                                                                  •Drag Capabilities
                                  Airframe Models                                 •Responsiveness

                                                                                                                            •Deflection capabilities
                                                                                                                            •Responsiveness
               Crew
               Capabilities
               - accuracy
               - perception
               - stamina
                                                                                                                  Engine Models
               - re -action
               times
               - SOP’s
                                                                     •Braking performance
                                                                     •Steering capabilities
                Human Models
                                                                     •Traction
                                                                                                                   •Thrust performance
                                                                     •Dampening capabilities
                                                                                                                   •Reverse Thrust performance
                                                                                                                   •Responsiveness
                                          Landing Gear Models                                                      •Fuel Consumption

                  Whole  system
                   It takes         simulations
                            a distributed        areorganization
                                            virtual  produced by tocoupling
                                                                    design,
                             all ofbuild
                   simulate and      the sub -systemsystem
                                         a complex    simulations
                                                           like an aircraft
©2008 metrum research group LLC       http://grids.ucs.indiana.edu/ptliupages/presentations/cendiapril25-05.ppt                                        3
PKPD in Proof of Concept Trials: IMMPACT 2008

                                                                       PROGRESSION
          Pharmacometrics…the science of

                                                                         DISEASE
          interpreting and describing
          pharmacology in a quantitative fashion
          (e.g. through modeling and simulation)

        DOSE                           CONCENTRATION                    RESPONSE

                                  PK                        PD

              TRIAL DESIGNS &
           DEVELOPMENT STRATEGY                                KNOWLEDGE

©2008 metrum research group LLC                                                                 4
PKPD in Proof of Concept Trials: IMMPACT 2008

             Modeling and Simulation: A Tool to Facilitate
                    the Learn-Confirm Continuum
             Sheiner LB. Learning versus confirming in clinical drug development.
             Clin Pharmacol Ther 1997; 61(3):275-91.

                                        Collect data

                          Build models to describe data and
                               confirm prior knowledge

                       Use M&S to learn from new data and
                            explore future outcomes

                                  Make informed decisions

                            Perform new experiment (study)

©2008 metrum research group LLC                                                                         5
PKPD in Proof of Concept Trials: IMMPACT 2008

                         M&S Throughout Drug Development

     Therapeutic Area                                                            Simulation & Optimization
     Knowledge: Disease                                                          of Phase III Trial Designs
                                                 Simulation-Guided
     Progression &
                                                 (Adaptive) Phase II
     Target Response
                                                 Designs: Early                              Pop PK, E-R for
     Profile
                                                 Probability of Success &                    Labeling and
                                                 Dose-Response                               Confirmatory
                                                                                             Efficacy Support
   Preclinical &
   Early Development:
   PK-PD, Systems                               Proof of Concept:
   Biology M&S                                  Probability-Based
                                                Decision Rule

  Toxicology            Human               Biomarker, Efficacy,     Efficacy,                  New
  PK                    MTD, PK             Tolerability E-R         Safety & Dose              Formulations
  Biomarker             Biomarker,          Dose-Response            Special                    Bridge to New
  E-R                   Tolerability, E-R   Covariates, Pop PK-PD    Populations                Indications

©2008 metrum research group LLC                                                                                      6
PKPD in Proof of Concept Trials: IMMPACT 2008

                                                                                                    What to Learn?

                                                 30

                                                                           30

                                                                                                                       WR Immediate

                                                                                                                                                            WR Immediate
                                                                                                                                                 10

                                                                                                                                                                                            10
                  LPS (min)

                                                           LPS (min)
                      Tolerability PD Efficacy
                                                 20

                                                                           20

                                                                                                                                                 8

                                                                                                                                                                                             8
                                                                                                                                                                      Prob (AE)
                                                                                                                                                 6

                                                                                                                                                                                             6
                                                 10

                                                                           10

                                                                                                                                                 4

                                                                                                                                                                                             4
                                                  5

                                                                            5

                                                                                                                                                 2

                                                                                                                                                                                             2
                                                  0

                                                                            0

                                                                                                                                                 0

                                                                                                                                                                                             0
                                                 450

                                                                           450

                                                                                                                                                 10

                                                                                                                                                                                            10
                                                                                                                                 WR 0.5 hr

                                                                                                                                                                      WR 0.5 hr
                  TST (min)

                                                           TST (min)
RESPONSE

                                                                                 LPSres$AUC               LPSres$AUC                                                                             WRres$AUC              WRres$AUC

                                                                                                                                                 8

                                                                                                                                                                                             8
                                                 430

                                                                           430

                                                                                                                                                 6

                                                                                                                                                                                             6
                                                                                                                                                                      Clinical Outcomes
           link

                                                 410

                                                                           410

                                                                                                                                                 4

                                                                                                                                                                                             4
                                                                                                                                                 2

                                                                                                                                                                                             2
                                                 390

                                                                           390

                                                                                                                                                 0

                                                                                                                                                                                             0
                                                 30

                                                                           30

                                                                                                                                                 10

                                                                                                                                                                                            10
                                                                                                                                      WR 7 hrs

                                                                                                                                                                           WR 7 hrs
                                                                                   NAW 2                    NAW 2
                                                 20

                                                                           20
                      Biomarkers

                                                                                 TSTres$AUC               TSTres$AUC                                                                             WRres$AUC              WRres$AUC

                                                                                                                                                 8

                                                                                                                                                                                             8
                          NAW

                                                                   NAW

                                                                                                                                                 6

                                                                                                                                                                                             6
                                                 10

                                                                           10

                                                                                                                                                 4

                                                                                                                                                                                             4
                                                  5

                                                                            5

                                                                                                                                                 2

                                                                                                                                                                                             2
                                                  0

                                                                            0

                                                                                                                                                 0

                                                                                                                                                                                             0
                                                                         NAW 1                      NAW 1
                                                 20

                                                                           20

                                                                                                                                                 20

                                                                                                                                                                                            20
                  Dose (mg)

                                                           Dose (mg)

                                                                                                                                 Dose (mg)

                                                                                                                                                                      Dose (mg)
                                                                            NAW1res$AUC               NAW1res$AUC                                                                                WRres$AUC              WRres$AUC
                                                 10

                                                                           10

                                                                                                                                                 10

                                                                                                                                                                                            10
                      Dose

                                                                                                                                                                      Dose
                                                  3

                                                                            3

                                                                                                                                                 3

                                                                                                                                                                                             3
                                                  1

                                                                            1

                                                                                                                                                 1

                                                                                                                                                                                             1

                                                       0                  50       0          100    50        150     100                            150
                                                                                                                                                       0                                    50     0         100   50       150     100   150

                                                                          EXPOSURE (e.g. AUC,    Cmax, Css avg)
                                                                                             NG2-73NG2-73
                                                                                           (ng*hr/mL)
                                                                         NG2-73 AUC (ng*hr/mL)              AUC (ng*hr/mL)
                                                                                                    AUC (ng*hr/mL)  NG2-73 AUC                                                            NG2-73 AUC (ng*hr/mL)
                                                                                                                                                                                                              NG2-73 AUC (ng*hr/mL)

©2008 metrum research group LLC                                                                                                                                                                                                                 7
PKPD in Proof of Concept Trials: IMMPACT 2008

                                   Regulatory Support for M&S

            -     Stanski. Model-Based Drug Development: A Critical Path Opportunity, March 18, 2004

                                         http://www.fda.gov/oc/initiatives/criticalpath/presentations.html

©2008 metrum research group LLC                                                                                                                 8
PKPD in Proof of Concept Trials: IMMPACT 2008

                                  Regulatory Support for M&S:
                                     Guidance Documents
        - Population Pharmacokinetics (FDA and EMEA)
        - Exposure-Response Relationships (FDA)
        - Dose-Response Information to Support Drug
          Registration (ICH-E4)
        - General Considerations for the Clinical Evaluation of Drugs (FDA 77-
          3040)
        - General Considerations for Pediatric Pharmacokinetic Studies (FDA)
        - Pharmacokinetics in Patients with Impaired Renal Function (FDA)
        - Pharmacokinetics in Patients With Impaired Hepatic Function (FDA)
        - Studies in Support of Special Populations:
          Geriatrics (ICH-E7)
        - Ethnic Factors in the Acceptability of Foreign
          Clinical Data (ICH-E5)
        - Clinical Investigation of Medicinal Products in the Pediatric Population
          (ICH-E11)
©2008 metrum research group LLC                                                                     9
PKPD in Proof of Concept Trials: IMMPACT 2008

                                  Determination of PoC
        - Primary Challenge: Define decision criteria for PoC
          determination
                Proof of mechanism
                Statistically significant efficacy response with approval endpoint
                Acceptable probability of achieving multivariate target response
                 profile
                Comparability to active control

        - Once defined, probability of meeting PoC decision criteria
          for different trial designs can be explored through
          modeling and simulation

©2008 metrum research group LLC                                                                         10
PKPD in Proof of Concept Trials: IMMPACT 2008

                                                                               Target Response Profile

                                               30

                                                                         30

                                                                                                                     WR Immediate

                                                                                                                                                          WR Immediate
                                                                                                                                               10

                                                                                                                                                                                          10
                LPS (min)

                                                         LPS (min)
                    Tolerability PD Efficacy
                                               20

                                                                         20

                                                                                                                                               8

                                                                                                                                                                                           8
                                                                                                                                                                     Prob (AE)
                                                                                                                                               6

                                                                                                                                                                                           6
                                               10

                                                                         10

                                                                                                                                               4

                                                                                                                                                                                           4
                                                5

                                                                          5

                                                                                                                                               2

                                                                                                                                                                                           2
                                                0

                                                                          0

                                                                                                                                               0

                                                                                                                                                                                           0
                                               450

                                                                         450

                                                                                                                                               10

                                                                                                                                                                                          10
                                                                                                                               WR 0.5 hr

                                                                                                                                                                    WR 0.5 hr
                TST (min)

                                                         TST (min)
RESPONSE

                                                                               LPSres$AUC               LPSres$AUC                                                                             WRres$AUC              WRres$AUC

                                                                                                                                               8

                                                                                                                                                                                           8
                                               430

                                                                         430

                                                                                                                                               6

                                                                                                                                                                                           6
                                                                                                                                                                    Clinical Outcomes
                                               410

                                                                         410

                                                                                                                                               4

                                                                                                                                                                                           4
                                                                                                                                               2

                                                                                                                                                                                           2
                                               390

                                                                         390

                                                                                                                                               0

                                                                                                                                                                                           0
                                               30

                                                                         30

                                                                                                                                               10

                                                                                                                                                                                          10
                                                                                                                                    WR 7 hrs

                                                                                                                                                                         WR 7 hrs
                                                                                 NAW 2                    NAW 2
                                               20

                                                                         20
                    Biomarkers

                                                                               TSTres$AUC               TSTres$AUC                                                                             WRres$AUC              WRres$AUC

                                                                                                                                               8

                                                                                                                                                                                           8
                            NAW

                                                                 NAW

                                                                                                                                               6

                                                                                                                                                                                           6
                                               10

                                                                         10

                                                                                                                                               4

                                                                                                                                                                                           4
                                                5

                                                                          5

                                                                                                                                               2

                                                                                                                                                                                           2
                                                0

                                                                          0

                                                                                                                                               0

                                                                                                                                                                                           0
                                                                       NAW 1                      NAW 1
                                               20

                                                                         20

                                                                                                                                               20

                                                                                                                                                                                          20
                Dose (mg)

                                                         Dose (mg)

                                                                                                                               Dose (mg)

                                                                                                                                                                    Dose (mg)
                                                                          NAW1res$AUC               NAW1res$AUC                                                                                WRres$AUC              WRres$AUC
                                               10

                                                                         10

                                                                                                                                               10

                                                                                                                                                                                          10
                    Dose

                                                                                                                                                                    Dose
                                                3

                                                                          3

                                                                                                                                               3

                                                                                                                                                                                           3
                                                1

                                                                          1

                                                                                                                                               1

                                                                                                                                                                                           1

                                                     0                  50       0          100    50        150     100                            150
                                                                                                                                                     0                                    50     0         100   50       150     100   150

                                                                        EXPOSURE (e.g. AUC,    Cmax, Css avg)
                                                                                           NG2-73NG2-73
                                                                                         (ng*hr/mL)
                                                                       NG2-73 AUC (ng*hr/mL)              AUC (ng*hr/mL)
                                                                                                  AUC (ng*hr/mL)  NG2-73 AUC                                                            NG2-73 AUC (ng*hr/mL)
                                                                                                                                                                                                            NG2-73 AUC (ng*hr/mL)
©2008 metrum research group LLC                                                                                                                                                                                                               11
PKPD in Proof of Concept Trials: IMMPACT 2008

                             PK and Exposure-Response M&S
                                  Opportunities in PoC
        - PK Modeling
                Understand PK in target population and possibly reduce inter-
                 individual variability in exposure to increase signal/noise: dosing
                 individualization
                Select PoC doses with minimal exposure overlap
                Explain unexpected outcomes (e.g. unknown phenotypic
                 differences in PK)
                Adjust for formulation differences
        - E-R Modeling
                Assessment of E-R relationships for multiple endpoints (e.g. after
                 dose-ranging based on efficacy endpoint)
                Basis for trial simulations: explore performance/options in silico
                 before initiating clinical trial

©2008 metrum research group LLC                                                                          12
PKPD in Proof of Concept Trials: IMMPACT 2008

              Impact of E-R Varies with PoC Trial Designs
            MTD-Type PoC Design
                            Typically 1 active treatment dose vs. reference
                             treatment
                            Dose selected based on Phase I MTD
                            Standard pair-wise statistical comparison
            Dose-Ranging PoC Design
                            Multiple doses investigated
                            Dose-range informed by preclinical data, Phase
                             I, biomarker, competitor data
                            Model-based data analysis
                            Often multi-variable PoC assessment

©2008 metrum research group LLC                                                                       13
PKPD in Proof of Concept Trials: IMMPACT 2008

                     Exposure-Response in MTD-Type PoC:
                            Proceed with Caution
        - Single active treatment arm at
          MTD (300 mg) vs. Placebo
        - Obtain PK in all individuals
        - Explore resulting relationship
          between exposure (Cavg) and
          Response (1 observation per
          individual)

        - Can we make an accurate
          assessment of the PK-PD
          relationship from this design?

    Problem described in: Nedelman JR, Rubin DB, Sheiner LB. Diagnostics for confounding in
    PK/PD models for oxcarbazepine. Stat Med. 2007 Jan 30;26(2):290-308.

©2008 metrum research group LLC                                                                       14
PKPD in Proof of Concept Trials: IMMPACT 2008

                      Exposure-Response in MTD-Type PoC
        - Consider possible inter-individual correlation between PK
          and PD

©2008 metrum research group LLC                                                           15
PKPD in Proof of Concept Trials: IMMPACT 2008

                      Exposure-Response in MTD-Type PoC

        - Resulting exposure-response relationships are misleading

©2008 metrum research group LLC                                                          16
PKPD in Proof of Concept Trials: IMMPACT 2008

                      Exposure-Response in MTD-Type PoC
        - One solution: Obtain within-individual E-R (e.g. crossover)
          analyzed with mixed-effects modeling

©2008 metrum research group LLC                                                            17
PKPD in Proof of Concept Trials: IMMPACT 2008

                      Exposure-Response in MTD-Type PoC
        - Another solution: Population E-R with broad dose-range

©2008 metrum research group LLC                                                          18
PKPD in Proof of Concept Trials: IMMPACT 2008

              PK-PD in Planning and Design of PoC Trials

        - Use prior information, when available

              Phase              I PK, tolerability, biomarkers
              Pre-clinical  estimates of effective concentrations,
                 relative potency
              Competitor             data
              Therapeutic             area knowledge

©2008 metrum research group LLC                                                                             19
PKPD in Proof of Concept Trials: IMMPACT 2008

                Toxicity E-R to Inform PoC Dose Selection

                                               Data from SAD, MAD
                                               in healthy volunteers

©2008 metrum research group LLC                                                       20
PKPD in Proof of Concept Trials: IMMPACT 2008

                                  Probability of QTc Prolongation

                • Explore probability of QTc – related toxicity at
                various doses from Phase I data
                • Project QTc prolongation at expected Cmax, given
                top dose and DDI
                • Define dose-limit and early probability of
                compound viability

©2008 metrum research group LLC                                                                    21
PKPD in Proof of Concept Trials: IMMPACT 2008

             Modeling Biomarker Data: Phase I MD Study
            -     PK-PD relationship evident & quantifiable (‘Emax’ model)
            -     Establish target PoM
            -     Set doses for investigation in PoC = concentrations within apparent
                  efficacious range
                                  7
                                                       E * Conc                       O     Placebo
                                  6
                                          Marker = E0 + max                           O     Dose 1
                                                       EC50 + Conc                    O     Dose 2
                                                                                      O     Dose 3
                                  5                                                   ---   Model Prediction
                         Marker

                                  4

                                  3

                                  2

                                  1

                                  0

                                      0          1        2           3      4
                                                      Concentration

©2008 metrum research group LLC                                                                                    22
PKPD in Proof of Concept Trials: IMMPACT 2008

                                  E-R Analysis of PoC Trials

        - Example
                Parallel groups: 4 active doses + placebo + active control
                 (competing therapy)

                Multiple Endpoints: biomarker 1 (efficacy), biomarker 2
                 (undesired), clinical outcome 1

                PoC determination based on model-based posterior probability of
                 reaching target response profile

©2008 metrum research group LLC                                                                        23
PKPD in Proof of Concept Trials: IMMPACT 2008

                                               E-R Based PoC: Test & Active Comparator
                                                   Response: Biomarker 1 (efficacy)
                                           - Drug X (red) was more potent than Comparator Y (blue)
                                           - Relative potencies (EC50 of X vs. Y) very
                                                                             Drug       consistent across
                                                                                  X (red),Comparator Y (blue) multiple response variables
                                           5

                                                                        Median observation at each collection time for each treatment (circles)
                                                                                        PK-PD Model Prediction (solid line)
                                                                                                EC50 = dashed lines
                    Biomarker 1 Response
                                           4

                                                    RXij = E0i + EMAXi*Ci/(EC50Xi + Ci) + eij
  Median Response

                                                    RYij = E0i + EMAXi*Ci/(EC50Yi + Ci) + eij
                                           3
                                           2

                                                                                                                                                                  Target
                                           1
                                           0

                                                                      Plasma Drug  Concentration
                                                                                Median Concentration

©2008 metrum research group LLC                                                                                                                                             24
PKPD in Proof of Concept Trials: IMMPACT 2008

                        PoC: E-R for Biomarker 2 (undesired)
              - Identified Drug X concentrations associated with BM II effect
              - Consider doses that provide for target concentrations

                          Concentration range                   Concentration range
                       associated with “no effect”             associated with “effect”
           Marker II

                                                                                                               Target

                                                   Concentration

©2008 metrum research group LLC                                                                                          25
PKPD in Proof of Concept Trials: IMMPACT 2008

                                  E-R for Clinical Outcome I
               Response I

                                                                                             Target
                Dose

                                         Cmax (concentration)
                                               Drug X

©2008 metrum research group LLC                                                                          26
PKPD in Proof of Concept Trials: IMMPACT 2008

                             Building Knowledge for Phase 2b

        -     Drug X posterior probability distribution for target response meets
              PoC criterion, but which doses should go into Phase 2b, where
              primary endpoint will be an approval outcome measure?

        -     Comparator Y Dose-Response
                    Literature data
                    Model = Nonlinear ‘Emax’ model for mean relationship
                    Uncertainty range: Based on standard errors of parameter estimates

        -     Scaled for Approximate Dose-Response of Drug X
                    Based on biomarker relative EC50 of Drug X vs. Comparator Y
                    Accounted for PK differences
                    Additional variability for uncertainty in scaling ratios

©2008 metrum research group LLC                                                                                   27
PKPD in Proof of Concept Trials: IMMPACT 2008

          Dose-Response Model for Comparator Y: 2b Response
                             0

                             1
                  Response

                                                  Literature data (o)
       Response

                             2

                                                                                           Uncertainty
                             3                                                             range: based
                                                                                           on 95% CI’s of
                                                                                           parameter
                                          Mean Prediction (___)                            estimates
                             4

                                  0   1       2                   3                4
                                            Dose
                                            Dose Y

©2008 metrum research group LLC                                                                                  28
PKPD in Proof of Concept Trials: IMMPACT 2008

                            Scaled Dose-Response for Drug X:
                                 Predicted 2b Response
                  - Select doses to further characterize (reduce uncertainty in) response surface

                        0

                        1
       Response

                        2

                        3

                        4
                             0            1             2             3                    4

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

                                                       Dose
©2008 metrum research group LLC                                                                                    29
PKPD in Proof of Concept Trials: IMMPACT 2008

         Other Examples of E-R in Analgesic PoC Trials

        - Dissociation of rescue drug effects from test treatment

        - Model-based inferences with dropout (missing data)

©2008 metrum research group LLC                                                            30
PKPD in Proof of Concept Trials: IMMPACT 2008

                         Dissociating Treatment Effects from
                                Rescue Dose Effects
        - Chronic pain PoC design (PBO plus 4 dose levels)
        - Acetaminophen rescue (500 mg) allowed as needed
        - Reduction in pain intensity is primary endpoint
        - Problem: How to interpret pain response in presence of rescue?

        - Proposal: Analyze entire data set with model-based analysis using 2
          simultaneous exposure-response relationships:
                Study Drug E-R
                Rescue E-R

©2008 metrum research group LLC                                                                      31
PKPD in Proof of Concept Trials: IMMPACT 2008

                                            Consideration
            - Potential delay between plasma exposure and exposure at
              site of action (e.g.,CNS)
                    May be more pronounced with
                       ▶   with acute or ‘prn’ dosing
                       ▶   shorter t1/2 and/or rapid Tmax

                                                            Figure from: Shinoda S, Aoyama T, Aoyama Y, Tomioka S, Matsumoto
                                                            Y, Ohe Y 2007. Pharmacokinetics/pharmacodynamics of acetaminophen
                                                            analgesia in Japanese patients with chronic pain. Biol Pharm Bull
                                                            30(1):157-161

                                                            Also see: Staahl C, Upton R, Foster DJ, Christrup LL, Kristensen K,
                                                            Hansen SH, Arendt-Nielsen L, Drewes AM. Pharmacokinetic-
                                                            pharmacodynamic modeling of morphine and oxycodone concentrations
                                                            and analgesic effect in a multimodal experimental pain model. J Clin
                                                            Pharmacol. 2008 May;48(5):619-31.

©2008 metrum research group LLC                                                                                                32
PKPD in Proof of Concept Trials: IMMPACT 2008

                                       Dual E-R Model Schematic
         Study                                                     Rescue
       Drug dose                                                  Drug dose

           Gut                    Central           Peripheral       Gut                   Central

                                                                                      PD Effect
                                        PD Effect

                 Effect                                          Effect

                                            Total Observed PD Response
©2008 metrum research group LLC                                                                                    33
PKPD in Proof of Concept Trials: IMMPACT 2008

               Individual Contributions to Total Response
   - Integrated model of
     Study Drug and Rescue
     E-R
   - Allows interpretation of
     individual and joint
     effects
   - Success of this
     approach highly
     dependent on adequate
     Dose-Ranging design
   - Results preliminary:
     Evaluation of
     performance through
     simulation ongoing

©2008 metrum research group LLC                                                      34
PKPD in Proof of Concept Trials: IMMPACT 2008

               Model-Based Inferences in the Presence of
                               Dropout
        - Acute pain PoC study

        - Dropout after first rescue

        - Population nonlinear-mixed effects exposure-response model
          developed from observed repeated-measures data (missing At
          random assumption)

        Approach first described in:
           Sheiner LB. A new approach to the analysis of analgesic drug trials,
           illustrated with bromfenac data. Clin Pharmacol Ther. 1994
           Sep;56(3):309-22.

©2008 metrum research group LLC                                                                     35
PKPD in Proof of Concept Trials: IMMPACT 2008
 NPRS Score Frequency (%)

                            NPRS Score Frequency (%)
                                                                                                     Observed Pain Intensity                             Observed Data
                                                                             100
                                                                                                      120Observed
                                                                                                         mg Patients (n=66)
                                                                                                                  Pain Intensity
                                                                                                                               Placebo
                                                                                            100
                                                                               80                                             Placebo (n=34)

                                                                                              80
                                                                         of NPRS20Score
                                                                                                                                                                                                                                                       Rescued                NPRS = 5
                                                                                      60

                                                                                                                                                                                                                                                       NPRS = 10
                                                                                                                                                                                                                                                         Rescued              NPRS
                                                                                                                                                                                                                                                                               NPRS= =4 5
                                                                                              60

                                                                                                                                                                                                                                                       NPRS = 9               NPRS = 3
                                                                                   40

                                                                                                                                                                                                                                                         NPRS = 10             NPRS = 4
                                                                                                                                                                                                                                                       NPRS = 8= 9
                                                                                                                                                                                                                                                         NPRS                 NPRS
                                                                                                                                                                                                                                                                               NPRS= =2 3
                                                                                              40

                                                                                                                                                                                                                                                       NPRS = 7= 8
                                                                                                                                                                                                                                                         NPRS                 NPRS
                                                                                                                                                                                                                                                                               NPRS= =1 2
                                                                                                                                                                                                                                                       NPRS = 6= 7
                                                                                                                                                                                                                                                         NPRS                 NPRS
                                                                                                                                                                                                                                                                               NPRS= =0 1
                                                                                              20

                                                                                                                                                                                                                                                         NPRS = 6              NPRS = 0
                                                                                 0

                                                                                                0

                                                                                                                                                                     NPRS Score Frequency (%)
                                    NPRS Score Frequency (%)

                                                                                           0.25                     1    2 4 6 8 10 12
                                                                                                                 0.25     1 2 4 6 8 10 12
                                                                                                                           Time (hr)Pain Intensity
                                                                                                                        Observed                                                                                                                     Observed Pain Intensity
                                                                                                                              Dose    1 (n=66)                                                                                                            Dose
                                                                                                                                                                                                                                                            Patients2(n=65)
 NPRS Score Frequency (%)

                                                                                                                                                               NPRS Score Frequency (%)
                                                                                                                                Time (hr)
                                                               Frequency
                                                                                                 100

                                                                                                                         120 mg Patients

                                                                                                                                                                                                                            100
                                                                                                                                                                                                                                                      60 mg
                            NPRS Score Frequency (%)

                                                                                                                                                                                           NPRS Score Frequency (%)

                                                                                                       Predicted Pain Intensity                                                                                                                  Extrapolated Pain Intensity
                                                                                                            80

                                                                                                                                                                                                                                          80
                                                                                                        120Predicted Pain(n=66)
                                                                                                                           Intensity                                                                                                               Extrapolated Pain(n=66)
                                                                                                                                                                                                                                                                     Intensity
                                                                    100

                                                                                                                                                                                                                      40 20 60 40 80 60 100
                                                                                                           mg Patients                                                                                                                             120 mg Patients
                                                                                                        100

                                                                                                                                                                                                                                       100
                                                                                                               Placebo (n=34)                                                                                                                            Placebo (n=34)
                                                                                                                                                                                                                                                            Rescued                NPRS = 5                    Rescued
                                                                                                      60
                                                                 80

                                                                                                                                                                                                                                                            NPRS = 10              NPRS = 4                    NPRS = 10
                                                                                                   80

                                                                                                                                                                                                                                          80                NPRS = 9               NPRS = 3                    NPRS = 9
                                                                                                 40

                                                                                                                                                                                                                                                            NPRS = 8               NPRS = 2                    NPRS = 8
                                                                               60

                                                                                              60

                                                                                                                                                                                                                                          60

                                                                                                                                                                                                                                                            NPRS = 7               NPRS = 1                    NPRS = 7
                                                                                            20

                                                                                                                                                                                                                                                            NPRS = 6               NPRS = 0                    NPRS = 6
                                                                               40

                                                                                              40

                                                                                                                                                                                                                                          40
                                                                                                      0

                                                                                                                                                                                                                                  0
                                                                               20

                                                                                                                                                                                                                        20
                                                                                              20

                                                                                                                                                                                                                                          20

                                                                                                                  0.25        1        2        4        6    8                  10 12                                                          0.25    1     2     4     6    8     10 12
                                                                                 0

                                                                                                                                                                                                                            0
                                                                                                0

                                                                                                                                                                                                                                               0

                                                                                                                                           Time (hr)                                                                                                              Time (hr)
                                        equency (%)

                                                                                                                                                                                                       equency (%)
                                                                                                                                                                            equency (%)

                                                                                                                                                                                                                                                                                       equency (%)
©2008 metrum research group LLC 0.25
                          0.25     1                                                                                     21       42       64       86       10
                                                                                                                                                             8 12
                                                                                                                                                                10 12                                                                          0.250.25 1 1 2 2 4 4 6 6 8 8 1010 1212                            36

                                                                                                                        Predicted Pain Intensity                                                                                                      Extrapolated
                                                                                                                                                                                                                                                     Predicted PainPain   Intensity
                                                                                                                                                                                                                                                                     Intensity                             Extrapolated Pai
                                                                                                                           Time Time
                                                                                                                                (hr) (hr)                                                                                                                    Time (hr)
                                                                                                                                                                                                                                                               Time (hr)
                                                                                                 100

                                                                                                                                                                                                                                               100
                                                                                                                                                                                                                            100

                                                                                                                                                                                                                                                                                                     100
                                                                                                                         120 mg Patients (n=66)                                                                                                       60120
                                                                                                                                                                                                                                                         mgmg   Patients
                                                                                                                                                                                                                                                             Patients      (n=66)
                                                                                                                                                                                                                                                                        (n=65)                               60 mg Patient
PKPD in Proof of Concept Trials: IMMPACT 2008

                                                          PD Response Time-Course
                                                          PI121 ID=2036                                     PI121 ID=2037                                           PI121 ID=2038

                                Pain Intensity

                                                                                  Pain Intensity

                                                                                                                                          Pain Intensity
                                                 10

                                                                                                   10

                                                                                                                                                           10
                                                 8

                                                                                                   8

                                                                                                                                                           8
                                                 6

                                                                                                   6

                                                                                                                                                           6
                                                 4

                                                                                                   4

                                                                                                                                                           4
                     Pain Intensity (NPRS)
                                                 2

                                                                                                   2

                                                                                                                                                           2
                                                 0

                                                                                                   0

                                                                                                                                                           0
                                                      0   2   4   6   8   10 12                         0   2   4   6       8   10   12                         0   2   4   6   8   10   12

                                                              Time (hr)                                         Time (hr)                                               Time (hr)

                                                          PI121 ID=2039                                     PI121 ID=2040                                           PI121 ID=2041
                                Pain Intensity

                                                                                  Pain Intensity

                                                                                                                                          Pain Intensity
                                                 10

                                                                                                   10

                                                                                                                                                           10
                                                 8

                                                                                                   8

                                                                                                                                                           8
                                                 6

                                                                                                   6

                                                                                                                                                           6
                                                 4

                                                                                                   4

                                                                                                                                                           4
                                                 2

                                                                                                   2

                                                                                                                                                           2
                                                 0

                                                                                                   0

                                                                                                                                                           0
                                                      0   2   4   6   8   10 12                         0   2   4   6       8   10   12                         0   2   4   6   8   10   12

                                                              Time (hr)                                         Time (hr)                                               Time (hr)

                                                          PI121 ID=2042                                     PI121 ID=2043                                           PI121 ID=2044
                                Pain Intensity

                                                                                  Pain Intensity

                                                                                                                                          Pain Intensity
                                                 10

                                                                                                   10

                                                                                                                                                           10
                                                 8

                                                                                                   8

                                                                                                                                                           8
                                                 6

                                                                                                   6

                                                                                                                                                           6
                                                 4

                                                                                                   4

                                                                                                                                                           4
                                                 2

                                                                                                   2

                                                                                                                                                           2
                                                 0

                                                                                                   0

                                                                                                                                                           0

                                                      0   2   4   6   8   10 12                         0   2   4   6       8   10   12                         0   2   4   6   8   10   12

                                                              Time (hr)                                         Time (hr)                                               Time (hr)

©2008 metrum research group LLC                                                                                                                                                                          37
NPRS Score Frequency (%)
                                                                                                                                                                                                                                         PKPD in Proof of Concept Trials: IMMPACT 2008

                                          Predicted Pain Intensity                                                                                                                                                                     Predicted Pain Intensity
                                                         Model-Based Extrapolation
                                           60 mg Patients (n=65)                                                                                                                                                                        120 mg Patients (n=66)
                            100

                                                                                                                                                                                   100
                            60

                                                                                                                                                                                   60
                                                                     NPRS Score Frequency (%)

                                                                                                                                                                                                          NPRS Score Frequency (%)
                            - Repeated-measures nonlinear mixed effects model used                                                      Predicted Pain Intensity
                                                                                                                                         60 mg Patients (n=65)
                                                                                                                                                                                                                                                                  Predicted Pain Intensity
                                                                                                                                                                                                                                                                   120 mg Patients (n=66)
                            20

                                                                                                                                                                                   20
                                                                                                    100

                                                                                                                                                                                                                                             100
                              to extrapolate individual responses over time
                             0

                                                                                                                                                                                    0
                                                                                                    60

                                                                                                                                                                                                                                             60
                            - View  simulated    6 response12 time-course  in1 the
                                                                                 2 absence     of

                                                                                                    20

                                                                                                                                                                                                                                             20
                               0.25  1 2   4         8  10            0.25           4     6 8 10                                                                                                                                                                                                 12

                              dropout

                                                                                                     0

                                                                                                                                                                                                                                              0
                                                                                                            NPRS Score Frequency (%)
                                         Time (hr)                                 Time (hr)              0.25                           1      2    4                       6           8           10        12                                      0.25        1   2    4       6   8    10   12
  Frequency of NPRS Score

                                                                     NPRS Score Frequency (%)

                                                                                                                                                                                                          NPRS Score Frequency (%)
                                                                                                                                                         Frequency of NPRS Score
                                                                                                                                                    Time (hr)                                                                                                              Time (hr)

                                         Extrapolated Pain Intensity                                                                   Extrapolated Pain Intensity                                                                   ExtrapolatedExtrapolated
                                                                                                                                                                                                                                                   Pain Intensity
                                                                                                                                                                                                                                                              Pain Intensity
                                           60 mgDose    1 (n=65)
                                                  Patients                                                                                                                                                                             120 mgDose
                                                                                                                                                                                                                                              Patients  2Patients
                                                                                                                                                                                                                                                           (n=66)
                            100

                                                                                                                                                                                   100
                                                                                                                                         60 mg Patients (n=65)                                                                                     120 mg          (n=66)
                                                                                                    100

                                                                                                                                                                                                                                             100
                                                                                                    60

                                                                                                                                                                                                                                             60
                            60

                                                                                                                                                                                   60
                                                                                                    20

                                                                                                                                                                                                                                             20
                                                                                                     0

                                                                                                                                                                                                                                              0
                            20

                                                                                                                                                                                   20
                                                                                                          0.25                           1      2    4                       6           8           10        12                                      0.25        1   2    4       6   8    10   12

                                                                                                                                                    Time (hr)                                                                                                              Time (hr)
                             0

                                                                                                                                                                                    0

                                  0.25     1      2       4      6                              8   10           12                                                                              0.25                                   1          2          4        6        8       10        12
                                                                                                                                             Rescued                               NPRS      =   5
                                                         Time (hr)                                                                           NPRS = 10                             NPRS      =   4                                                        Time (hr)
                                                                                                                                             NPRS = 9                              NPRS      =   3
                                                                                                                                             NPRS = 8                              NPRS      =   2
                                                                                                                                             NPRS = 7                              NPRS      =   1
                                                                                                                                             NPRS = 6                              NPRS      =   0

©2008 metrum research group LLC                                                                                                                                                                                                                                                                        38

                                               Rescued               NPRS = 5
PKPD in Proof of Concept Trials: IMMPACT 2008

                                       Summary (1)
        The utility of exposure-response in PoC trials depends on
         study design and PoC goals.
        - MTD-Type PoC
                E-R modeling of PoC data has minimal value; may be misleading
                PK modeling still useful for understanding target population PK,
                 reducing variability, or for explaining extreme outcomes
        - Dose-Ranging PoC
                E-R has high value for design, analysis and PoC determination
                Comparative E-R relationships across multiple endpoints/active
                 controls provides insight into probability of achieving target product
                 profile
                Advances knowledge building for future drug development phases
                Basis for trial simulations to explore future designs
©2008 metrum research group LLC                                                                          39
PKPD in Proof of Concept Trials: IMMPACT 2008

                                        Summary (2)

        - PK and E-R modeling and simulation:
                are tools for knowledge-building and decision support in drug
                 development
                provide basis for trial simulations to explore and optimize trial
                 design performance
                are best supported by trial designs that explore individual E-R
                 relationships
                of multiple endpoints allows quantitative assessment of drug’s
                 multivariate response profile, supporting dose-selection decisions
                may be useful in assessing test treatment response in presence of
                 rescue dosing (preliminary)
                may be useful for making inferences in the presence of dropout
                 (for non-regulatory purposes)

©2008 metrum research group LLC                                                                           40
PKPD in Proof of Concept Trials: IMMPACT 2008

                                          Additional References
            -     Krall RL, KH Engleman, HC Ko, and CC Peck. “Clinical Trial Modeling and Simulation – Warner KE, Peck
                  CC, Work in Progress.” /Drug Info J/, 32: 971-976, 1998.
            -     Peck CC. “Drug development: Improving the process.” /Food and Drug Law J/. 52 (2):163-167, 1997.
            -     Reigner BG, PEO Williams, IH Patel, J-L Steimer, CC Peck, and P van Brummelen. “An evaluation of the
                  integration of pharmacokinetic and pharmacodynamic principles in clinical drug development.” /Clin
                  Pharmacokinet/, 33(2): 142-52, 1997.
            -      Biomarkers Definitions Working Group. “Biomarkers and surrogate endpoints: Preferred definitions and
                  conceptual framework.” /Clin Pharm Ther/ 69 (3): 89-95, 2001.
            -     Galluppi GR, MC Rogge, LK Roskos, LJ Lesko, MD Green, DW Feigal, and CC Peck. “Integration of
                  pharmacokinetics and pharmacodynamics studies in the discovery, development and review of protein
                  therapeutic agents: a conference report.” /Clin Pharm Ther/, 2001.
            -     Holford NHG, JPR Monteleone, HC Kimko, and CC Peck. “Simulation of Clinical Trials” in /Annual Rev
                  Pharmacol Toxicol./ Vol. 40: 209-234, 2000.
            -     Lockwood, Ewy, Herman, Holford. Application of Clinical Trial Simulation to Compare Proof of Concept
                  Designs for Drugs with a Slow Onset of Effect; An Example in Alzheimer’s Disease. Pharm Res. 23:9, 2006.
            -     Klingenberg B. A Unified Framework for Proof of Concept and Dose Estimation with Categorical Responses.
                  www.williams.edu/~bklingen .
            -     Lalonde RL, Kowalski KG, Hutmacher MM, Ewy W, Nichols DJ, Milligan PA, Corrigan BW, Lockwood PA,
                  Marshall SA, Benincosa LJ, Tensfeldt TG, Parivar K, Amantea M, Glue P, Koide H, Miller R. Model-based
                  drug development. Clin Pharmacol Ther. 2007 Jul;82(1):21-32.
            -     Atkinson AJ Jr, Lalonde RL.Introduction of quantitative methods in pharmacology and clinical pharmacology:
                  a historical overview. Clin Pharmacol Ther. 2007 Jul;82(1):3-6.

            FDA Presentations on Model-Based Drug Development
            -     http://www.fda.gov/oc/initiatives/criticalpath/presentations.html
            -     http://www.fda.gov/ohrms/dockets/ac/03/slides/3998s1.htm
            -     http://www.aapspharmaceutica.com/meetings/files/38/Booth.ppt

©2008 metrum research group LLC                                                                                                    41
PKPD in Proof of Concept Trials: IMMPACT 2008

                                  Acknowledgements

            - Heidi Costa
            - Leonid Gibiansky
            - Bill Knebel
            - Matthew Riggs
            - Bill Gillespie

            - Industry collaborators

©2008 metrum research group LLC                                                           42
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