Backgrou ground Small molecule from the CNS portfolio Phase 1 - - PowerPoint PPT Presentation

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Dec 09, 2022 299 likes •394 views

Ph2 h2a d dose ose sele selection b base ased on on the r he rela elationship b bet etween PK an and Tar arget Occup ccupancy cy CNS Session - EMA/EFPIA Workshop on the importance of Dose finding and dose selection London,

SLIDE 1

Ph2 h2a d dose

se sele

selection b base ased on

n the r

he rela elationship b bet etween PK an and Tar arget Occup ccupancy cy

CNS Session - EMA/EFPIA Workshop on the importance of Dose finding and dose selection London, December 5 2014 Mona Alameddine and Patricia Sanwald Ducray

SLIDE 2

Backgrou ground

Small molecule from the CNS portfolio
Phase 1 studies completed in healthy volunteers:

– Single ascending dose – Multiple ascending dose – PET study

Uncertainty around the target occupancy (TO) needed at steady

state for efficacy in the patient population

Which doses should be tested in Phase 2a to characterize the TO

– Efficacy relationship?

SLIDE 3

Clin inica ical P l Pharmac macolo logy prop

pos
sals
To build a Population Pharmacokinetic model using Phase 1 data
To build a PKPD model for target occupancy using PET data
To simulate Target Occupancy time profiles at steady-state by dose
To compute the % of measurements where Target Occupancy was within

given ranges over the dosing interval

To determine the optimal number of doses that should be tested in

Phase 2a to characterize the TO – Efficacy relationship

SLIDE 4

PK PK and PK PKPD PD mod

dels
A two-compartment Population PK model with first order absorption adequately described the PK profile

LAGTIME Cen Central V2/F /F Per eripher heral V3/F /F CL CL/F Dos Dose

Gut

Q/F /F Ka

An Emax PKPD model adequately described the PK/Target Occupancy relationship

SLIDE 5

Si Simulated T Target Occ Occupancy ti time profiles a at Ste Steady State te

Perc ercen entage of

f hou
url

rly s simulated ed mea easure remen ents with thin TO ra ranges es

TO TO Rang anges 10 10-30% 0% T TO 30 30-50% 0% T TO 50 50-80% 0% T TO Dose 1 1

52 1

Dose 2 2

10 48 42

Median 95% Prediction Interval Median 95% Prediction Interval

SLIDE 6

Optimal c covera rage ge of Target O Occu cupan ancy cy achieved wi with 3 3 dose

SLIDE 7

Conclu clusio ions

Population PK and PKPD models were used to simulate Target Occupancy

time profiles at steady state by dose

Doses that cover optimally the target occupancy ranges over the dosing

interval were identified

Phase 1 data were leveraged using simple modeling methods that translated

into powerful graphical representation to support dose selection

Team was open and valued the recommendation

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