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 2

When not to use Systems Pharmacology for dose selection? ? RESPONSE DOSE Compound A with unknown mechanism of action showed a dose-independent efficacy in the rat model of infra-red-light induced schizophrenia 3

Unprecedented V The Low-hanging Challenge fruit Uncertainty of dose Need prediction Academic Waste of time interest X X Precedented NO Pharmacology YES MOA quantitatively understood Opportunity/Feasibility 4

Unprecedented TRK-A FAAH Uncertainty PTH(1-84) of dose Need prediction Precedented NO Pharmacology YES MOA quantitatively understood Opportunity/Feasibility 5

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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 Predicted Systems Equivalent TRK-A dose (exposure) NGF mAb Pharmacology pathway (exposure) response (dpERK) Clinical Efficacy 8

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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Systems-pharmacology-model predicted elevations of CNS CB1 receptor occupancy by AEA following a single dose of PF-04457845 PF-04457845 (mg) 25 0.1 0.3 1 CB1 receptor occupancy (%) 3 20 10 20 40 15 10 5 0 0 50 100 150 200 250 300 350 Time after dose (h)

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Unprecedented TRK-A FAAH Uncertainty PTH(1-84) of dose Need prediction Precedented NO Pharmacology YES MOA quantitatively understood Opportunity/Feasibility 13

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