title: Confirmatory population pharmacokinetic analysis for bapineuzumab phase 3 studies in patients with mild to moderate Alzheimer's disease.
abstract: The population pharmacokinetics of bapineuzumab, a humanized monoclonal IgG1 antibody that was generated from a murine monoclonal antibody and binds specifically to amino acids 1 to 5 of the free N-terminus of human amyloid-beta peptide, were characterized in patients with mild-to-moderate alzheimer's disease in two Phase 3 studies (ELN115727-301 and ELN115727-302). A total of 8,040 serum concentration measurements were analyzed from 1,458 patients who received 6 doses of bapineuzumab intravenously once every 13 weeks. A confirmatory analysis was conducted using a prespecified two-compartment model with first-order elimination. After the primary covariate effect assessment, a reduced model was obtained. Based on the reduced model, the typical population values for clearance (CL) and volume (Vc ) from the central compartment in a Caucasian subject with a standardized body weight of 70 kg were 0.17 L/day and 3.13 L, respectively. Bapineuzumab CL and Vc increased with body weight. Furthermore, CL was 15% higher in non-Caucasian subjects; however, this was not considered clinically relevant. None of the other evaluated covariates had a meaningful impact on CL. The median terminal elimination half-life was estimated to be approximately 29 days. Sensitivity analyses and bootstrapping results supported model stability.
authors.affiliation: Model Based Drug Development, Janssen Research and Development, LLC, Spring House, PA, USA.
authors.forename: Chuanpu
authors.initials: C
authors.lastname: Hu
authors.forename: Omoniyi
authors.initials: O
authors.lastname: Adedokun
authors.forename: Kaori
authors.initials: K
authors.lastname: Ito
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Raje
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018697:Nootropic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018697:Nootropic Agents; C545458:bapineuzumab
keywords: Type I error; bapineusumab; confirmatory approach; nonlinear mixed effect modeling; population pharmacokinetics