Open AccessIn silico exploration of amyloid‐related imaging abnormalities in the gantenerumab open‐label extension trials using a semi‐mechanistic model
Author(s) -
Aldea Roxana,
Grimm Hans Peter,
Gieschke Ronald,
Hofmann Carsten,
Lott Dominik,
Bullain Szofia,
Delmar Paul,
Klein Gregory,
Lyons Marco,
Piazza Fabrizio,
Carare Roxana O.,
Mazer Norman A.
Publication year - 2022
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1002/trc2.12306
Subject(s) - in silico , extension (predicate logic) , amyloid (mycology) , computational biology , neuroscience , computer science , artificial intelligence , chemistry , biology , medicine , pathology , biochemistry , programming language , gene
Amyloid‐related imaging abnormalities with edema/effusion (ARIA‐E) are commonly observed with anti‐amyloid therapies in Alzheimer's disease. We developed a semi‐mechanistic, in silico model to understand the time course of ARIA‐E and its dose dependency. Methods Dynamic and statistical analyses of data from 112 individuals that experienced ARIA‐E in the open‐label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer's disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer's disease) studies were used for model building. Gantenerumab pharmacokinetics, local amyloid removal, disturbance and repair of the vascular wall, and ARIA‐E magnitude were represented in the novel vascular wall disturbance (VWD) model of ARIA‐E. Results The modeled individual‐level profiles provided a good representation of the observed pharmacokinetics and time course of ARIA‐E magnitude. ARIA‐E dynamics were shown to depend on the interplay between drug‐mediated amyloid removal and intrinsic vascular repair processes. Discussion Upon further refinement and validation, the VWD model could inform strategies for dosing and ARIA monitoring in individuals with an ARIA‐E history.