imaging in drug development
TRANSCRIPT
The Drug Response Pathway
Clinical Outcome Drug in
Blood
Drug in Tissue
Drug at Target
2nd Messenger Response
Tissue Response
Physiological/Behavioural Response
The Drug Response Pathway
Clinical Outcome Drug in
Blood
Drug in Tissue
Drug at Target
2nd Messenger Response
Tissue Response
Physiological/Behavioural Response
Imaging
Quantifying drug-target engagement to refine the dose range
Imaging The Drug
- Biodistribution
Imaging The Target
- Occupancy Measures brain uptake of the radiolabelled drug candidate
Measures the change in target availability post drug administration
Provides a measure of “free” drug concentration (VF)
Provides direct measure of target occupancy by the drug (DVS)
Requires radiolabelling of the drug candidate with a positron emitting nucleide - often feasible
Requires a usable radioligand – often unavailable
Text to go here. Lorum ipsum caecillia hort
servus et atrium ae. Servus horum ae
ipsum sit ammer dolor atrium. Lorum ipsum
ae et servum atrium.
Quantification of Radiotracer Binding
VNS
VF
VS VT
Total Signal
Text to go here. Lorum ipsum caecillia hort
servus et atrium ae. Servus horum ae
ipsum sit ammer dolor atrium. Lorum ipsum
ae et servum atrium.
Quantification of Radiotracer Binding
VNS
VF
VS VT
Total Signal Suitable Radioligand
VNS
VF
VS
Occupancy Study
Text to go here. Lorum ipsum caecillia hort
servus et atrium ae. Servus horum ae
ipsum sit ammer dolor atrium. Lorum ipsum
ae et servum atrium.
Quantification of Radiotracer Binding
VNS
VF
VS VT
Total Signal Suitable Radioligand
VNS
VF
VS
Labelled Drug
VNS
VF
VS
Occupancy Study
Biodistribution
Brain Penetration
A - Brain penetration – candidate selection - [Free Drug] brain – single dose-occupancy prediction
Pig
1
2
3
4
5
6
brain
1
2
3
4
5
6
1
2
3
4
5
6
Better predictive value of higher species for human BBB penetration
Species variability in CNS penetration
Rat Pig Human
Characterisation of BBB Transport
A - Brain penetration – candidate selection - [Free Drug] brain – single dose-occupancy prediction
Label the target: Drug occupancy
Baseline
Plasma Conc
Occu
pa
ncy
B
A
B
A
Post Drug
Radioligand Drug Target
B - Time-occupancy relationship - single dose-occupancy measurement
- repeat dose-occupancy prediction Abanades, JCBFM 2011; Salinas, JCBFM 2013
Quantification of Target Engagement
B - Time-occupancy relationship - single dose-occupancy measurement
- repeat dose-occupancy prediction
Plasma PK PET Occupancy PK/RO Model
Model I: “Direct”
Cp - EC50 Model
Model II: “Indirect”
kon - koff Limited Model
50ECtC
tCtTOC
P
P
ROkRORCk
dt
dROoffTPon
Quantification of Target Engagement – Study Design
• Repeat dose occupancy - Closer to the clinical situation - Cannot be performed early in the development cycle - May obtain biased results due to changes in baseline target number
• Single dose occupancy - Maximum impact - can be performed parallel with FTIH safety study - Time-dose-occupancy estimation - definition of pharmacokinetic model - Combined with repeat-dose plasma pharmacokinetics allows prediction of repeat dose occupancy
• Healthy volunteers vs patients - Same “free” drug concentration, Same target structure = No Difference
B - Time-occupancy relationship - single dose-occupancy measurement
- repeat dose-occupancy prediction Abanades, JCBFM 2011; Salinas, JCBFM 2013