Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease

Alzheimers Res Ther. 2020 Jan 22;12(1):16. doi: 10.1186/s13195-020-0580-2.


Background: Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric Aβ(1-40) and Aβ(1-42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study.

Methods: In ABBY, BLAZE, and GN29632 studies, patients with mild-to-moderate AD were treated with either placebo or crenezumab (300 mg subcutaneously every 2 weeks [q2w], or 15 mg/kg, 30 mg/kg, 45 mg/kg, 60 mg/kg, or 120 mg/kg intravenously q4w). Serum/plasma PK/PD analyses included samples from 131 patients who received crenezumab in all three studies. CSF PK/PD analyses included samples from 76 patients who received crenezumab in ABBY or BLAZE. The impact of baseline patient factors on Aβ profiles was also evaluated.

Results: The serum concentration of crenezumab increased in a dose-proportional manner between 15 and 120 mg/kg q4w. Total monomeric plasma Aβ(1-40) and Aβ(1-42) levels significantly increased after crenezumab administration. The mean crenezumab CSF to serum ratio was ~ 0.3% and was similar across dosing cohorts/routes of administration. No clear correlation was observed between crenezumab concentration and Aβ(1-42) increase in CSF at week 69. The target-mediated drug disposition (TMDD) model described the observed plasma concentration-time profiles of crenezumab and Aβ well. Elimination clearance (CLel) and central volume of distribution (Vcent) of crenezumab were estimated at 0.159 L/day and 2.89 L, respectively, corresponding to a half-life of ~ 20 days. Subcutaneous bioavailability was estimated at 66.2%.

Conclusions: Crenezumab PK was dose proportional up to 120 mg/kg, with a half-life consistent with IgG monoclonal antibodies. Our findings provide evidence for peripheral target engagement in patients with mild-to-moderate AD. The study also showed that a model-based approach is useful in making inference on PK/PD relationship with unmeasured species such as free plasma Aβ levels.

Trial registrations: ABBY:, NCT01343966. Registered April 28, 2011.

Blaze:, NCT01397578. Registered July 19, 2011. GN29632:, NCT02353598. Registered February 3, 2015.

Keywords: Nonlinear mixed-effects modeling; PK/PD; Pharmacokinetics; Plasma beta-amyloid; Target-mediated drug disposition model.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / blood*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Antibodies, Monoclonal, Humanized / pharmacokinetics*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged


  • Amyloid beta-Peptides
  • Antibodies, Monoclonal, Humanized
  • crenezumab

Associated data