Receptor pharmacology or animal models for dose selection in humans?

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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
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Animal Models?
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Predictive Modelling in Early Development.

• A Simulation exercise Extrapolation!
• May include some analysis of data.
• Prediction of Dose
• Pharmacological
• Clinical
• HUMAN DOSE!

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Why predicting Human Clinical Dose early?
TI
adapted from Jennifer Sims, ABPI/BIA Early
Clinical Trials Taskforce, slideset
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The Dose is RightPharmas Favourite Game Show
Predicting Human Dose? Simple.
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
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Mechanistic Classification of Biomarkers
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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
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Species differences in Receptors
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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

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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

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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, BP
• Assumption re. PgP

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Using Receptor Occupancy for a new target
Page satellite meeting, Pamplona, 2005
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Using primary Human Pharmacology and Clinical
Knowledge

Huntjens et al. Rheumatology 200544846859
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Primary Pharmacology different Human vs Animal
Gone horribly wrong
X
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Receptor Occupancy of TGN1412 at starting Dose
Jennifer Sims, ABPI/BIA Early Clinical Trials
Taskforce, slideset
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Mechanism of Action of TGN1412
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Predictive animal model
Rocchetti et al. Eur J Cancer 43 (2007) 1862-8
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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!

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My Favourite Animal Model