(T-105) Characterizing Chimeric Aducanumab Disposition in a Preclinical Alzheimer’s Model Using Population PK Modeling

NITIN CHARBE – School of Medicine – INDIANA UNIVERSITY; Lais Da Silva – School of Medicine – INDIANA UNIVERSITY; Emma Doud – School of Medicine – INDIANA UNIVERSITY; Kasi Hansen – School of Medicine – INDIANA UNIVERSITY; Kathryn Haynes – School of Medicine – University of Pittsburgh; Kierra Eldridge – School of Medicine – INDIANA UNIVERSITY; Amber Mosley – School of Medicine – INDIANA UNIVERSITY; Stacey Sukoff Rizzo – School of Medicine – University of Pittsburgh; Michael Heathman – School of Medicine – INDIANA UNIVERSITY; Paul R Territo – School of Medicine – INDIANA UNIVERSITY; Sara Quinney – School of Medicine – INDIANA UNIVERSITY

Objectives: Alzheimer’s disease (AD) continues to pose a significant public health burden, with few available treatments that effectively modify disease progression. Aducanumab, a monoclonal antibody targeting beta-amyloid plaques, has shown limited potential in clinical trials, and was approved by the US FDA in 2021. To support translational research, the MODEL-AD Preclinical Testing Core has established a comprehensive pipeline to evaluate pharmacokinetic and pharmacodynamic (PK/PD) responses in validated AD mouse models. As part of this pipeline’s validation, a chimeric (ch) murinized form of Aducanumab was tested in 5xFAD transgenic mice. The study encompassed formulation development, multi-dose PK screening, disease-modification assessments using PET/CT imaging, and functional assays to determine therapeutic efficacy. To support efficacy work in model system, primary objective of this abstract was to characterize the PK/PD profile of chAducanumab in the 5xFAD model.

Methods: Male and female 5xFAD mice received intra-peritoneal chAducanumab at 0.1,1.0, 1.56, or 30 mg/kg. Plasma concentrations were quantified by PRM LC-MS/MS. A PopPK model was developed using Monolix (Lixoft, France), employing a one-compartment model with first-order kinetics. Absorption rate (ka) was fixed and volume of distribution (V), clearance (Cl), interindividual variability (ΩV, ΩCl) and residual error (additive and proportional components) were estimated. Model qualification included goodness-of-fit plots and visual predictive checks. Data visualization was conducted in R (v4.2).

Results: In the final population model, the absorption-rate constant (ka) was fixed at 1.17 h⁻¹, a value obtained from a pilot data set that included time points spanning the absorption phase. Population estimates were, V = 0.01 L (RSE = 13%), Cl = 0.0029 L/week (RSE = 10.4%). Interindividual variability was moderate (ΩV = 0.85, ΩCl = 0.86), with acceptable precision (RSEs = 12.3% and 9.1%, respectively). Residual variability in the concentration–time data was most accurately described by a combined error model incorporating both proportional and additive terms. The proportional error was 0.33 (CV = 10.6 %), and the additive error was 0.22 (CV = 5.9 %). Goodness-of-fit diagnostics and visual predictive checks demonstrated strong agreement between observed data and both population-level and individual model predictions.

Conclusions: A one-compartment PopPK model effectively characterized chAducanumab disposition in the 5xFAD mouse model. As part of the MODEL-AD preclinical pipeline for monoclonal antibodies, these results support the use of this model in future translational efforts. Development and integration of QSP modeling will further enable the investigation of sex-dependent PK mechanisms, enhancing the translational relevance of 5xFAD in Alzheimer’s research.

Citations: Budd Haeberlein, S., Aisen, P. S., Barkhof, F.,et al. (2022). Journal of Prevention of Alzheimer’s Disease, 9(2), 197–210.
Toda, Y., Iwatsubo, T., Nakamura, Y.,et al . (2024). The Journal of Prevention of Alzheimer’s Disease, 11(5), 1260–1269.

Keywords: Aducanumab, popPK, 5xFAD mice