P4-312: A model-based comparison of the nonclinical and clinical effects of anti-Aβ antibodies on plasma Aβ1-40 levels

Abstract

Administration of anti–Aβ antibodies to animals and humans produces increases in the total levels of Aβ in the plasma. This biomarker response provides evidence that the antibodies ‘hit the target’ and also provides insight for comparison of effects between species. Although difficult to measure directly, an understanding of antibody effects on ‘free’ Aβ levels would also be advantageous, as one of the desired effects of antibody administration is to decrease ‘free’ Aβ levels and shift Aβ equilibria away from deposition into plaque. Mechanism–based pharmacokinetic/pharmacodynamic (PK/PD) models were developed to characterize relationships between plasma anti–Aβ antibody levels and the time–course of the plasma Aβ1–40 response in PDAPP mice and Alzheimer's patients. These models allow inference of effects on both ‘total’ and ‘free’ Aβ. Simulations were performed to compare the relative biomarker responses in PDAPP mice and humans. Following intraperitoneal administration of anti–Aβ antibodies (m266) to PDAPP mice, plasma m266 concentrations showed first–order absorption followed by mono–exponential decay. In humans, intravenous anti–Aβ antibody administration led to bi–exponential pharmacokinetics that were well characterized using a 2–compartment PK model. In both mice and humans, antibody concentrations appeared to increase proportionally with administered dose. Dose–dependant plasma Aβ1–40 pharmacodynamic responses were observed in both mice and humans. These PD responses were well characterized using mechanism–based PK/PD models that incorporated antibody–antigen binding principles. Simulation results showed greater effects on ‘free’ Aβ1–40 at the dose levels administered in humans than for the dose levels used for nonclinical efficacy studies in PDAPP mice. This analysis illustrates that the dose levels studied in the initial clinical study compare favorably, from a biomarker perspective, with dose levels that demonstrated beneficial effects in PDAPP mice.