1. Receptor pharmacology or animal models for dose selection in humans? Bart Laurijssens Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, UK Satellite Meeting on Predictive Modelling in Drug Development PAGE, St Petersburg, 23 June 2009

2. 2 Animal Models? Pharmacology

3. 3 Predictive Modelling in Early Development.  A Simulation exercise: Extrapolation!  May include some analysis of data.  Prediction of Dose  Pharmacological  Clinical  HUMAN DOSE!

4. 4 Why predicting Human Clinical Dose early? [adapted from: Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset] TI

5. 5 ParameterGuessLowHigh MWT450250700 Kd(nM)10.3100 Clinical103100 CL(ml/min)20031000 F (%)64%5%95% Tau (hrs)12624 No prior knowledge! The Dose is Right Pharma’s Favourite Game Show Bob Barker  Why is the dose “mg” not grams or “ng”?  The screening process naturally selects candidates that drive the dose range  A model can help Dose  MWT Kd Clinical CL/F  [thanks to Daren Austin] Predicting Human Dose? Simple.

6. 6 Mechanistic Classification of Biomarkers Ease to Predict Clinical Relevance of Prediction? ?

7. 7 DRUG Affinity Intrinsic Efficacy SYSTEM Slope Potency Intrinsic Activity Tissue species gender Disease Age chronic treatment combined treatment Pharmacodynamic Theory [Van der Graaf & Danhof, 1998]

8. 8 Species differences in Receptors

9. 9 So what about Animal Models of Disease?  Face Validity  Phenomenological Similarities with the disorder  Predictive Validity  Need drugs that work  Quantitative  False positives/negatives  Mechanism specific?  Construct Validity  Sound theoretical rationale  Need to understand disease and animal

10. 10 What information to look for?  Distribution to target(s) in Humans:  Transporters (eg PgP)  Extracellular vs Intracellular target  Interaction with the Human Target(s)  Affinity (in vitro, ex vivo)  Efficacy (agonism vs antagonism)  Human pharmacology  In vitro, ex vivo  Animal models of physiology (or Disease)  Time course of response  Knowledge  Experience with mechanism in Humans  Human physiology  General Pharmacological Theory

11. 11  Human PK-RO was predicted using:  Rat ex-vivo RO for R1  Rat and Human in-vitro Binding (R1 and R2)  Rat and Human Fu, B:P  Assumption re. PgP Using Receptor Occupancy for a new target

12. 12 Using Receptor Occupancy for a new target Minimal “response” during dosing interval at steady state 2] Do not study doses with <80% RO 3] Doses that hardly separate based on RO, potentially separate in efficacy [Page satellite meeting, Pamplona, 2005] 1] =theoretical range of efficacy: No suppression – No effect Max suppression – Max effect

13. 13 Total Unbound Ketorolac Fenoprof en Naproxe n Rofecoxib Using primary Human Pharmacology and Clinical Knowledge [Huntjens et al. Rheumatology 2005;44:846–859]

14. 14 Primary Pharmacology different Human vs Animal Gone horribly wrong X

15. 15 Receptor Occupancy of TGN1412 at starting Dose [Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset]

16. 16 Mechanism of Action of TGN1412

17. 17 Predictive animal model [Rocchetti et al. Eur J Cancer 43 (2007): 1862-8]

18. 18

19. 19 Conclusions  It is not about animal models vs receptor occupancy, but about what data is informative.  Only informative data is worthy of your modelling skills and time.  Animal Models MAY be informative  Human Target Receptor Occupancy, or if possible, Target (in)Activation, is always informative.  And … nearly always available.  HUMAN dose!

20. 20 My Favourite Animal Model