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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?
?
DOSE
RESPONSE
Compound A with unknown mechanism of action showed a dose-independent efficacy in the rat model of infra-red-light induced schizophrenia
3
Opportunity/Feasibility
Need
MOA quantitatively understood
Uncertainty of dose
prediction
NO Pharmacology YES Precedented
Unprecedented
X
V
X Waste of time
Academic interest
Low-hanging fruit
The Challenge
4
Opportunity/Feasibility
Need
MOA quantitatively understood
Uncertainty of dose
prediction
NO Pharmacology YES Precedented
Unprecedented
PTH(1-84)
TRK-A
FAAH
5
6
7
8
• 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
10
0 50 100 150 200 250 300 350Time after dose (h)
0
5
10
15
20
25
CB1
rece
ptor
occ
upan
cy (%
)
0.10.313102040
PF-04457845 (mg)
Systems-pharmacology-model predicted elevations of CNS CB1 receptor occupancy by AEA following a single dose of PF-04457845
www.xenologiq.com Quantitative drug discovery solutions
Opportunity/Feasibility
Need
MOA quantitatively understood
Uncertainty of dose
prediction
NO Pharmacology YES Precedented
Unprecedented
PTH(1-84)
TRK-A
FAAH
13
www.nature.com/psp
14
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