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

BACKGROUND: Crenezumab, a fully humanized anti-beta-amyloid (Aß) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aß. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric Aß(1-40) and Aß(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 Aß 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 Aß(1-40) and Aß(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 Aß(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 Aß 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 Aß levels. TRIAL REGISTRATIONS: ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. BLAZE: ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.