Olivier J David (1), Anthony Gebhart (2), Etienne Pigeolet (1)
(1) Pharmacometrics, Novartis, Basel, Switzerland, (2) Division of Pharmacology, University of Leiden, Netherlands
Objectives:
One important pathological feature of Alzheimer disease (AD) is the presence of deposits forming amyloid plaques in the brain cortex of affected individuals. These plaques are constituted of aggregated fibrils of Aβ peptides [1] thought to be involved in the pathophysiology of AD [2]. The amyloid cascade hypothesis [3] states that deposition of Aβ is a very early event in the pathogenesis of AD, and will ultimately lead to neurodegeneration and dementia of the Alzheimer type. Strategies that target decreasing the Aβ generated from amyloid precursor protein (APP) are potential therapeutics. APP is known to be cleaved by the α-secretase to form the sAPP-α protein and by the β-secretase (BACE-1) forming sAPPβ and C99 (other processes are likely involved). The latter is further cleaved to form the Aβ peptides.
CNP520 is an orally-available, centrally active and potent inhibitor of BACE-1. CNP520 by reducing Aβ generation and restoring Aβ equilibrium offers the promise of disease modification in AD.
The goal of this population pharmacokinetic/pharmacodynamic (PK/PD) analysis was to characterize simultaneously the dose-exposure and the exposure-response (cerebro-spinal fluid (CSF) concentrations of Aβ-40, sAPPα and sAPPβ peptides) of CNP520.
Methods:
The popPK/PD modeling was performed on clinical data from a first-in-human, single and multiple ascending oral dose study in healthy adult and elderly subjects (n>200).
The plasma CNP520 and CSF concentrations of the Aβ-40, sAPPα and sAPPβ peptides were fitted simultaneously to a PK/PD model using non-linear mixed-effects modelling implemented in Monolix 2016R1. Data preparation and graphical outputs were generated using R 3.2.3 (library ggplot2).
Results:
CNP520 PK was best described with a linear two-compartment model with an absorption lag time, sequential zero- and first-order absorption processes and first-order elimination. Plasma concentrations of CNP520 were well described and parameters estimated precisely.
The rate of production of APP was assumed to be constant and coded as a zero-order process. The elimination of APP was assumed to occur via the α-secretase or the BACE-1 only. The formation and the elimination of Aβ-40, sAPPα and sAPPβ peptides were assumed to be first-order processes.
The drug effect was modeled by linking plasma CNP520 concentrations to CSF Aβ-40 and sAPPβ concentrations via an indirect response population PK/PD model (Imax model with a Hill coefficient), in which CNP520 inhibited the sAPPβ and Aβ-40 synthesis and by indirect effect increased the production of sAPPα. This model estimated a maximal CSF sAPPβ and Aβ-40 inhibition (Imax) of more than 95% with a concentration associated with 50% of the maximum effect (IC50) of approximately 20 ng/mL. The model described adequately the concentrations of Aβ-40, sAPPα and sAPPβ peptides in CSF following CNP520 administration. The model parameters were estimated with a good precision (relative standard error less than 10% for most of them).
Conclusions: The plasma PK of CNP520 and its PD effects on three CSF peptides were modeled simultaneously. The model described the data adequately and can be used for further work, such as dose selection and recovery time to baseline values.
References:
[1] Masters CL, Beyreuther K (2006) Pathways to the discovery of the Aβ-amyloid of Alzheimer’s disease. J. Alzheimer’s Disease; 9 (Suppl. 3): 155-61.
[2] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science; 297: 353-56.
[3] Karran E, Mercken M, Strooper BD. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 2011; 10:698-712.
Reference: PAGE 27 (2018) Abstr 8725 [www.page-meeting.org/?abstract=8725]
Poster: Drug/Disease Modelling - CNS