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PBPK MODELLING OF THE BENZODIAZEP by hilen

VIEWS: 6 PAGES: 27

									    USING BIOMARKERS
                  FOR


EARLY PHASE DOSE SELECTION
                 WITH


PROTEIN ANTAGONIST DRUGS

              Ivan Nestorov
      ivan.nestorov@biogenidec.com
      TALK FRAMEWORK

• Setting the stage: introductions and definitions
• PK and binding as major early markers
• Biological activity as validation for binding
• Walk-through example
• Regulatory implications
      THERAPEUTIC PROTEINS
after B.M. Rao, D.A. Laufenburger, K.D. Wittrup. Integrating cell-level kinetic modeling into
 the design of engineered protein therapeutics. Nature Biotechnology. 23: 191-194, 2005.



• Antagonists (e.g. antibodies, soluble receptors) - block
  native protein interactions by binding to target protein(s)
      – Examples – anti-TNF, anti-VEGF, anti-BLyS/APRIL

• Agonists (e.g. cytokines, growth factors) - stimulate cell
  surface receptors
      – Examples – erythropoietin, rhGH, G-CSF, IL-2

• Targeting agents (e.g. antibodies, immunotoxins) –
  target specific cell surface antigens or deliver therapeutic
  agents
      – Examples – anti-CD20
        EXAMPLES:
BLYS/APRIL antagonist (atacicept)

   BLyS (BAFF)
                                          B cell differentiation
                                          B cell survival
                                          Antibody production
                        APRIL
                                          Ig class switch



   BAFF-R                              Heterotrimer




                 BCMA


    B-Cell

                                TACI
      THE RESPONSE CASCADE
  M Danhof, G Alvan, SG Dahl, J Kuhlmann, G Paintaud. Mechanism-based pharmacokinetic-
pharmacodynamic modeling-a new classification of biomarkers. Pharm Res. 2005; 22:1432-1437.




                               PHASE 1 DATA



   HOW TO USE THIS INFORMATION FOR
  DOSAGE REGIMEN DESIGN IN PHASE 2/3?
Atacicept exposure–response cascade (RA)
            FREE DRUG
           FREE TARGET             IgX             IgX RF      ESR, CRP       ACRXX%
             COMPLEX              FACS              ACPA      JOINT CNTS       DAS28


DOSE         BLyS/APRIL            MoA          Disease            Clinical    Clinical
& Freq.       Inhibition        Biomarkers     Biomarkers          Markers    Endpoints

          Binding &
          Inhibition

                Biological activity

                        Disease related activity

                                      Clinical activity


                                               Clinical efficacy
   THERAPEUTIC PROTEINS
• Large molecules, slow PK and PD
• Specific binding to targets dominant (by engineering)
• Target load often:
   –   Significant (in molar concentration terms)
   –   Distributed across various tissues
   –   Constantly renewed by endogenous production of targets
   –   Endogenous production may be boosted by depletion

• Nonspecific binding sometimes negligible (!!! check)
• No P450 metabolism, but Ab’s to drug possible
• Protein drug metabolism often capacity limited
      PK & TARGET BINDING:
         MAJOR EARLY MARKERS

• Free drug PK is expected to be nonlinear
  – Unless nonlinearity is overwhelmed
  – Or unless total drug is measured
  – PK Assays are critical

• Dosing should be targeted at the saturation
  – Below saturation – sub-therapeutic regimen
  – Above saturation – waste of drug and/or potential
    over-inhibition
  – Saturation – both in blood and tissues
  – Saturation is a dynamic process – at all times
                    PK & BINDING
BINDING EQUILIBRIUM:

• Binding affinity       ABSORPTION
                            SITE
• Drug & ligand




                                      BINDING TO
  concentrations




                                        L1 & L2
   – Systemically         BLOOD
   – In tissues

• Dosing schedule
                          TISSUES,
• Endogenous ligand          SoA
  production               FREE
   – Systemically         DRUG PK
   – In tissues
          PK, BINDING & DOSING
         OBJECTIVE:
• Adequate binding
   – Process in time             ABSORPTION
   – At Sites of Action             SITE

   – Not necessarily complete




                                              BINDING TO
     binding of ligand




                                                L1 & L2
• Markers of PK/binding           BLOOD
   – Free drug
   – Total drug
   – Complex concentration
   – Free ligand concentration    TISSUES,
                                     SoA
• Means to achieve goal:
   –   Type of dosing regimen      FREE
   –   Dosing levels              DRUG PK
   –   Dosing frequency
   –   Mode of administration
       ACCUMULATION OF COMPLEX
P.P. Tak, et al. Atacicept in patients with rheumatoid arthritis: an exploratory, multicenter, double -blind, placebo-controlled,
        dose – escalating, single and repeat dose phase 1b study. Accepted Arthr. & Rheum. ar-06-1723, 2007.



                                   1000
   Atacicept/BLyS Complex [U/mL]




                                    800



                                    600



                                    400



                                    200



                                      0
                                          0   14   28   42   56        70          84         98          112        126
                                                             Time [days]
BLyS Concentration after Rituximab in RA
G. Cambridge et al. Circulating Levels of B Lymphocyte Stimulator in Patients With Rheumatoid Arthritis
           Following Rituximab Treatment. Arthritis and Rheumatism 54: 723-732 (2006).




          BLyS accummulation rate in serum: ~0.08 ng/mL/day
       DESIGN SO FAR:
• Type of dosage: Loading - Maintenance
  – Eliminate initial target ligand load
  – Boost the redistribution of target ligand
  – Compensate endogenous ligand production

• Dose levels and dosing frequency ???
• Mode of administration: ???
                                            RECEPTOR MEDIATED PK
                                         A. Munafo, A. Priestley, I. Nestorov, J. Visich, M. Rogge. Safety, pharmacokinetics and
                                      pharmacodynamics of atacicept in healthy volunteers. Eur. J. Clin. Pharm. 63:647-656 (2007).


                                            Free Atacicept                                                                  Atacicept/BLyS Complex
                         100000                                                                                   300
                                                                        2.1 mg
                                                                        70 mg
                                                                        210 mg                                    250
                          10000
                                                                        630 mg




                                                                                  Atacicept:BLyS Complex [U/mL]
Free atacicept [ng/mL]




                                                                                                                  200

                           1000



                                                                                                                  150


                            100


                                                                                                                  100



                             10
                                                                                                                   50




                              1                                                                                     0
                                  0     7      14    21      28    35    42      49                                     0    50   100       150       200   250   300
                                                     Time [days]                                                                        Time [days]
                                         QUIZ:
                                  DOSING FREQUENCY?

              1000                                                                                            160

                                                                          Terminal Halflife:




                                                                                                                    Drug/Target complex [U/mL]
                                                                             20-30 days                       120
Free drug [ng/mL]




                    100


                                                                                   Free drug                  80

                                                                                   Drug/Target Complex
                     10
                                                                                                              40




                      1                                                                                       0
                          0   7    14   21   28   35       42        49      56   63     70     77       84
                                                       Time [days]
                                         QUIZ:
                                  DOSING FREQUENCY?

              1000                                                                                           160
                                                  30-40% incomplete
                                                      inhibition




                                                                                                                   Drug/Target complex [U/mL]
                                                                                                             120
Free drug [ng/mL]




                    100


                                                                                  Free drug                  80

                                                                                  Drug/Target Complex
                     10
                                                                                                             40


                                                   Next dose?
                      1                                                                                      0
                          0   7    14   21   28     35       42        49   56   63     70     77       84
                                                         Time [days]
                       Biological activity tracks target ligand binding
                                More frequent dosing at smaller doses yields better effect
                      120
                                                                                                                      750




                      100                                                                                             600




                                                                                      Atacicept:BLyS Complex [U/mL]
IgM [% of Baseline]




                      80                                                                                              450




                      60                                                                                              300




                      40                                                                                              150
                                                                   18 mg/kg IV
                                                                   4x3 mg/kg SC
                                                                   4x1 mg/kg SC
                      20                                                                                               0
                            0     7   14   21    28    35     42   49    56      63                                         0   7   14   21   28   35   42   49   56   63   70   77   84
                                                Time [days]                                                                                        Time [days]

                                       Biological Activity                                                                           Drug-Ligand Complex
             DESIGN SO FAR:
• Biological activity tracks binding
• Type of dosage: Loading - Maintenance
   – Eliminate initial ligand load
   – Boost the redistribution of ligand
   – Compensate endogenous ligand production

• Dose levels and dosing frequency
   – More frequent smaller doses yield higher biological activity
     compared to less frequent higher doses
   – Single dose saturation – between 75 and 210 mg
   – Dosing interval to maximize inhibition – 7 – 14 days
   – What doses / dosing intervals???

• Mode of administration: ???
S.C. ADMINISTRATION of
    PROTEIN DRUGS
                  • Uptake by lymphatic
                    system
                  • Poorly quantified
                  • Dependent on MW
                  • Lymphatic & blood
                    circulation closely
                    interwined
                  • Consider kinetic vs
                    dynamic rates
                  • Lymph can be SoA
 S.C. injection
                          COMPARING S.C. & I.V. ADMINISTRATION
                                      S.c. Atacicept systemic                                                             … but biological activity is the
                                          bioavailability is                                                                        same …
               1000000
                                           ~ 35 - 40% …                                                         120

                                                                      9 mg/kg S.C.

                         100000                                       9 mg/kg I.V.                              100
Free atacicept [ng/mL]




                                                                                          IgM [% of Baseline]
                         10000                                                                                  80




                          1000                                                                                  60




                           100                                                                                  40




                            10                                                                                  20
                                  0      7    14       21        28      35          42                               0     7     14       21        28   35   42
                                                                                                                                       Time [days]
                                                   Time [days]
                          COMPARING S.C. & I.V. ADMINISTRATION
                                      … because target binding is the same!
                  1000000                                                                                          400

                                                                   9 mg/kg S.C.

                                                                   9 mg/kg I.V.
                         100000




                                                                                   Atacicept:BLyS Complex [U/mL]
                                                                                                                   300
Free atacicept [ng/mL]




                          10000


                                                                                                                   200


                           1000



                                                                                                                   100
                            100




                             10                                                                                     0
                                  0    7   14       21        28      35          42                                     0   7   14       21        28   35   42
                                                Time [days]                                                                           Time [days]
          DESIGN SO FAR:
• Biological activity tracks binding
• Type of dosage: Loading - Maintenance
   – Eliminate initial ligand load
   – Boost the redistribution of ligand
   – Compensate endogenous ligand production

• Dose levels and dosing frequency
   – More frequent smaller doses yield higher biological
     activity compared to less frequent higher doses
   – Single dose saturation – between 75 and 210 mg
   – Dosing interval to maximize inhibition – 7 – 14 days
   – What doses / dosing intervals???

• Mode of administration: SC
                      TIME TO BECOME QUANTITATIVE…

          ATACICEPT Pop PK/PD MODEL
I. Nestorov et al. Population modeling of the relationship between TACI-Ig exposure and biomarker response in patients with
           rheumatoid arthritis (RA). Population Analysis Group in Europe meeting PAGE 2006, June 14-16, 2006.


             DOSE
                                                         CL

                              Ka                                         Q
              Abs.
                                               Central                                   Peripheral
              Site
                                        Vc                                          Vp




                             I max  C                   
                K syn  1 
                                                          
                                                                                               K off
                            IC 50  C                   
                                                                  IgM, IgG, IgA
 Simulations: Dose saturation of effect
                                Varying doses, same dosing frequency (QW)
                      100
                                                                                         25 mg
                                                                                         50 mg
                      80
                                                                                         75 mg
                                                                                         150 mg
IgM [% of baseline]




                      60                                                                 500 mg



                      40



                      20
                                                                       Going beyond 150 mg
                                                                        for QW not justified
                       0
                            0   14   28   42   56   70    84      98   112   126   140   154      168
                                                     T ime [ d ays]
          DESIGN COMPLETE
• Biological activity tracks binding
• Type of dosage: Loading - Maintenance
   – Eliminate initial ligand load
   – Boost the redistribution of ligand
   – Compensate endogenous ligand production

• Dose levels and dosing frequency
   – More frequent smaller doses yield higher biological activity
     compared to less frequent higher doses
   – Single dose saturation – between 75 and 210 mg
   – Dosing interval to maximize inhibition – 7 – 14 days
   – Dosing frequency – once weekly (QW)
   – Dose levels for Phase 2/3 study: 25, 75 and 150 mg

• Mode of administration: SC
REGULATORY ACTION
      PHASE 1
        CONCLUSIONS
• PK and target binding are major early
  biomarkers for protein antagonists

• Saturation of binding can be used for
  early phase dosage regimen design

• Population PK/PD modeling helps
  quantify saturation

• Mechanistic validation should be
  implemented as much as possible

								
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