title: Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.
abstract: OBJECTIVE
  PF-04360365 is a humanized IgG(2)Δa anti-amyloid β (Aβ) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects.
  
  
  METHODS
  30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year.
  
  
  RESULTS
  All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aβ species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms.
  
  
  CONCLUSIONS
  PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.
authors.forename: Izuru
authors.initials: I
authors.lastname: Miyoshi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Abe
authors.forename: Qinying
authors.initials: Q
authors.lastname: Zhao
authors.forename: Carol
authors.initials: C
authors.lastname: Cronenberger
authors.forename: Kanae
authors.initials: K
authors.lastname: Togo
authors.forename: Taro
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Martin M
authors.initials: MM
authors.lastname: Bednar
authors.forename: James W
authors.initials: JW
authors.lastname: Kupiec
authors.forename: Brendon
authors.initials: B
authors.lastname: Binneman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C572721:ponezumab