Population pharmacokinetics and standard uptake value ratio of aducanumab, an amyloid plaque–removing agent, in patients with Alzheimer’s disease

Abstract

Aducanumab is a human immunoglobulin G1 anti-amyloid beta (Aβ) antibody currently being evaluated for potential treatment of patients with early Alzheimer's disease. This paper describes the relationship between the population pharmacokinetics (PopPKs) and pharmacokinetics-pharmacodynamics (PKs-PDs) of aducanumab using data from phase I to III clinical studies, with standard uptake value ratio (SUVR) used as a PD marker. Across clinical studies, aducanumab was administered intravenously either as a single dose ranging from 0.3 to 60 mg/kg or as multiple doses of 1, 3, 6, or 10 mg/kg every 4 weeks. A titration regimen with maintenance doses of 3, 6, or 10 mg/kg was also evaluated.Aducanumab PK was characterized with a two-compartment model with firstorder elimination. No nonlinearities in PKs were observed. The PopPK-PD model was developed using a sequential estimation approach. The time course of amyloid plaques, as expressed by composite SUVR measured using positron emission tomography, was described using an indirect response model with drug effect stimulating the elimination of SUVR. None of the identified covariates on PK and the PopPK-PD model were clinically relevant. The PopPK-PD model showed that magnitude, duration, and consistency of dosing are important factors determining the degree of Aβ removal. The intrinsic pharmacology of aducanumab remained consistent across studies. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Two large, identical phase III trials of aducanumab, an IgG1 anti-amyloid beta (Aβ) antibody, showed differential removal of plaque and efficacy over 18 months of treatment.

Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease

“…T A B L E 2 Population PD parameters and bootstrap CIs for the final PK/PD model for Amyloid PET SUVr typical patient estimated from PK model is days, is similar with donanemab (10 days) 33 but shorter than aducanumab (24.8 days) 34 and gantenerumab (22 days). 35 Lecanemab CL and V 1 increased with increasing body weight with exponents of 0.403 and 0.606, respectively, and both parameters were slightly lower in women compared to men.…”

Quantitative systems pharmacology model for Alzheimer’s disease to predict the effect of aducanumab on brain amyloid

“… 29 Aducanumab PK characteristics were comparable with a typical IgG1 mAb and were well described by a two‐compartment PK model. 36 The CSF to plasma concentration ratio was approximately 0.5%, as aducanumab appears to have better brain penetration than other mAbs. 11 The plasma total Aβ measures both free Aβ and drug‐bound Aβ and increases post‐aducanumab dosing due to the Aβ‐drug complex having slower clearance compared with free Aβ.…”

A Time‐to‐Event Exposure‐Response Model for Amyloid‐Related Imaging Abnormalities Following Administration of Aducanumab to Subjects With Early Alzheimer Disease

“…Aducanumab PK was characterized by a linear 2‐compartment model with first‐order elimination. The model estimated mean (95% CI) half‐life and time to reach steady state are 24.8 (14.8‐37.9) days and ≈4 (2.42‐6.19) months, respectively 11,12 …”

“…Individual empirical Bayes estimates of the PK parameters from the PopPK model were used to predict aducanumab concentration‐time profiles for the analysis 11,12 …”

“…The model estimated mean (95% CI) half-life and time to reach steady state are 24.8 (14.8-37.9) days and ≈4 (2.42-6.19) months, respectively. 11,12 Individual empirical Bayes estimates of the PK parameters from the PopPK model were used to predict aducanumab concentration-time profiles for the analysis. 11,12 The ARIA-E event and time to resolution are measured by MRI and expressed as binary data, with 0 indicating the absence of ARIA-E and 1 indicating the presence of ARIA-E.…”