Imaging in Drug Development

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

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Quantification of Radiotracer Binding

VNS

VF

VS VT

Total Signal

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Quantification of Radiotracer Binding

VNS

VF

VS VT

Total Signal Suitable Radioligand

VNS

VF

VS

Occupancy Study

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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

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5

6

brain

1

2

3

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5

6

1

2

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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