Mona Alameddine, Christophe Boetsch, Ronan Carnac, Patricia Sanwald-Ducray and Nicolas Frey
Clinical Pharmacology, Roche Innovation Center Basel, F.Hoffmann-La Roche
Objectives: Target occupancy is a useful metric to confirm drug engagement with the target in early clinical phase and to potentially predict the expected clinical response in the target patient population. For most first in class compounds in Neuroscience there is usually a high uncertainty on the link between TO and the clinical response and it is a challenge to determine which doses should be tested in Phase 2. To help the project team to address this challenge for our drug X, a CNS small molecule currently in phase 1, we proposed to build a population pharmacokinetic (PK) model and an exposure-TO model and to combine them to determine using simulations the optimal number of doses that should be investigated in Phase 2.
Methods: Using Phase 1 PK data a Population PK model was build using NONMEM (Version 7.2.0). Using Phase 1 PET data an exposure- TO model was build using Phoenix NLME (Version 1.2). By combining those 2 models, 24-h steady-state TO time profiles were simulated for 7 different doses. For each dose, the percentages of hourly TO measurements within expected relevant region of interests, three non-overlapping 3 predefined ranges of TO (10-30%, 30-50%, 50-80%) were calculated and were used to select the number of doses to be investigated in Phase 2 to get an optimal coverage of the TO range and to properly characterize the TO-clinical response relationship.
Results: Rich Pharmacokinetic (PK) data from 95 individuals were adequately described by a two-compartment Population PK model with first order absorption and elimination. Body weight significantly impacted Inter-compartment Clearance and peripheral volume while age significantly affected peripheral volume. An Emax model adequately described the PKTO relationship using sparse PK and PET scans data in 9 individuals. TO simulations were performed using a distribution of covariate from a historical trial in the same target patient population in order to properly account for the covariate impact on PK. By comparing the results of the 7 simulated doses using graphical illustration, we determined that at least 3 doses should be investigated in Phase 2 to get an appropriate coverage of the overall TO range compared to 2 doses.
Conclusions: We successfully leveraged the target occupancy information collected in Phase 1 to identify the optimal number and strength of doses to be evaluated in Phase 2 to properly characterize the target occupancy-efficacy relationship that ensures later a robust dose selection rationale for the confirmatory trials.
Reference: PAGE 24 () Abstr 3351 [www.page-meeting.org/?abstract=3351]
Poster: Drug/Disease modeling - CNS