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?

Pharmacology

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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?

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

TI

5

-5%

5%

15%

25%

35%

45%

0.1 0.3 1 3 10 30 100 300 1000 3000

Dose (mg)

Pro

bab

ility

Parameter Guess Low High

MWT 450 250 700

Kd(nM) 1 0.3 100

Clinical 10 3 100

CL(ml/min) 200 3 1000

F (%) 64% 5% 95%

Tau (hrs) 12 6 24

No priorknowledge!

The Dose is RightPharma’s Favourite Game Show

BobBarker

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.

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Mechanistic Classification of Biomarkers

Ease to Predict

Clinical Relevance of Prediction?

?

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DRUG

Affinity

IntrinsicEfficacy

SYSTEM Slope

Potency

IntrinsicActivity

Tissue species gender

DiseaseAge

chronic treatment combined treatment

Pharmacodynamic Theory

[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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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

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Using Receptor Occupancy for a new target

Compound Dose (mg)

1 10 100

Ta

rge

t R

ec

ep

tor

oc

cu

pa

nc

y (

%,

95

% C

I)

0

10

20

30

40

50

60

70

80

90

100

NT

re

late

d r

es

po

ns

e (

%)

0

10

20

30

40

50

60

70

80

90

100

Target Receptor Occupancy

NT related response

Minimal “response” during dosing interval at steady state2] 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 effectMax suppression – Max effect

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Total Unbound

Ketorolac

Fenoprofen

Naproxen

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

15Receptor 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