A Systems Pharmacology Perspective on the Clinical Development of - - PowerPoint PPT Presentation

EMA-EFPIA Workshop Dose Selection and Dose-Exposure-Response Characterisation London 4-12-2014

A Systems Pharmacology Perspective on the Clinical Development of Fatty Acid Amide Hydrolase Inhibitors for Pain

Piet van der Graaf

Editor-in-Chief Leiden Academic Centre for Drug Research (LACDR) CPT: Pharmacometrics & Systems Pharmacology Leiden University, The Netherlands www.nature.com/psp p.vandergraaf@lacdr.leidenuniv.nl

Systems Pharmacology: Picking the right target

• Target Selection
• Generate hypotheses for novel drug targets
• Target Validation
• Further assess the potential of a novel drug

target

• Target Authorisation
• Assessment of novel therapeutic intervention

against product concept

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When not to use Systems Pharmacology for dose selection?

?

DOSE RESPONSE

Compound A with unknown mechanism of action showed a dose-independent efficacy in the rat model of infra-red-light induced schizophrenia

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Opportunity/Feasibility Need

MOA quantitatively understood Uncertainty

• f dose

prediction

NO Pharmacology YES Precedented Unprecedented

X V X

Waste of time Academic interest Low-hanging fruit

The Challenge

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Opportunity/Feasibility Need

MOA quantitatively understood Uncertainty

• f dose

prediction

NO Pharmacology YES Precedented Unprecedented

PTH(1-84) TRK-A FAAH

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• NGF mAbs clinically-

precedented efficacy

• Use Systems Pharmacology

model to dose predict for novel targets in NGF pathway (TRK-A)

• High need: balance efficacy

– potential CNS side effects TRK-A inhibitors

Known efficacious dose (exposure) NGF mAb Predicted Systems Pharmacology pathway response (dpERK) Equivalent TRK-A dose (exposure)

Clinical Efficacy

Dose Prediction for a TrkA Kinase Inhibitor versus a Compound that Binds NGF

Impact of a compound that binds NGF (green) versus TrkA kinase inhibitor with different pharmacological properties (red and blue) on the dppERK response Inset panel shows the drug PK in the interstitial fluid compartment

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50 100 150 200 250 300 350 Time after dose (h) 5 10 15 20 25 CB1 receptor occupancy (%)

0.1 0.3 1 3 10 20 40 PF-04457845 (mg)

Systems-pharmacology-model predicted elevations of CNS CB1 receptor

• ccupancy by AEA following a single dose of PF-04457845

www.xenologiq.com Quantitative drug discovery solutions

Opportunity/Feasibility Need

MOA quantitatively understood Uncertainty

• f dose

prediction

NO Pharmacology YES Precedented Unprecedented

PTH(1-84) TRK-A FAAH

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www.nature.com/psp

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