Receptor pharmacology or animal models for dose selection in humans?

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 DevelopmentPAGE, St Petersburg, 23 June 2009

2. Pharmacology Animal Models?

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

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

5. Predicting Human Dose? Simple. The Dose is RightPharma’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 No prior knowledge! Dose  MWT Kd Clinical CL/F  [thanks to Daren Austin]

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

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

8. Species differences in Receptors

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. 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. Using Receptor Occupancy for a new target • 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

12. 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 1] =theoretical range of efficacy: No suppression – No effect Max suppression – Max effect Using Receptor Occupancy for a new target [Page satellite meeting, Pamplona, 2005]

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

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

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

16. Mechanism of Action of TGN1412

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

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. My Favourite Animal Model