Gregory Z. Ferl, Angelica Quartino, Lee Honigberg, Saroja Ramanujan
Genentech, Inc.
Objectives: Our goal was to develop a mechanistic mathematical model capable of predicting neutralization of soluble monomeric Aβ in the brain, cerebrospinal fluid (CSF) and plasma during the course of Alzheimer’s disease therapy with anti-Aβ monoclonal antibodies (mAbs) that possess varying PK/PD properties.
Methods: We utilized physiologic information from the literature to develop a model structure and assign values to model parameters. Within the model structure and parameter space we address mechanisms related to nonsoluble Aβ species, transport rates of Aβ and the mAb-Aβ complex from brain to CSF, degradation rates of Aβ and the mAb-Aβ complex in brain, transport of Aβ across the blood brain barrier and steady state mAb concentration in brain.
Results: Our model is able to simulate steady-state, on-treatment mAb, Aβ and mAb-Aβ complex concentration-time profiles in brain, CSF and plasma, allowing us to explore the impact of antibody pharmacokinetics, Aβ binding affinity and other physiologic model parameters on percent neutralization of soluble monomeric Aβ in brain.
Conclusions: Based on our model, we were able to generate predictions regarding neutralization of soluble monomeric Aβ in brain during anti-Aβ mAb therapy and develop hypotheses regarding mechanisms that drive increased total Aβ concentrations which have been observed in CSF and plasma during treatment.
Reference: PAGE 24 () Abstr 3489 [www.page-meeting.org/?abstract=3489]
Poster: Drug/Disease modeling - CNS