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 Animal Models? Pharmacology

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? [adapted from: Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset] TI

5 ParameterGuessLowHigh MWT Kd(nM) Clinical CL(ml/min) 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 Mechanistic Classification of Biomarkers Ease to Predict Clinical Relevance of Prediction? ?

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 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  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 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 Total Unbound Ketorolac Fenoprof en Naproxe n Rofecoxib 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): ]

18

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