title: Population pharmacokinetics of golimumab in patients with ankylosing spondylitis: impact of body weight and immunogenicity.
abstract: OBJECTIVE
  To develop a population pharmacokinetic (PK) model of subcutaneously administered golimumab, a human anti-tumor necrosis factor monoclonal antibody, in patients with ankylosing spondylitis (AS), estimate typical fixed and random population PK parameters, and identify significant covariates on golimumab pharmacokinetics.
  
  
  METHODS
  Serum concentration data through Week 24 of a randomized, double-blind, placebo-controlled Phase III trial of golimumab (50 or 100 mg every 4 weeks) were analyzed using a nonlinear mixed-effects modeling approach. The effects of potential covariates on golimumab were evaluated.
  
  
  RESULTS
  A one-compartment PK model with first-order absorption and elimination was chosen to describe the observed golimumab concentration-time data in patients with AS. Population estimates obtained from the final model for a typical 70-kg patient were: apparent systemic clearance (CL/F), 1.41 l/day (95% confidence interval (CI): 1.31 - 1.51) and apparent volume of distribution (V/F), 22.6 L (95% CI: 20.7 - 24.4). The first-order absorption rate constant (Ka) was estimated to be 1.01 day-1 (95% CI: 0.760 - 1.46). The between-subject variabilities for CL/F, V/F, and Ka were 35.2%, 38.6%, and 78.6%, respectively. Body weight was the most significant covariate, affecting both CL/F and V/F. Antibody-to-golimumab status, baseline C-reactive protein level, and sex were also identified as significant covariates on CL/F.
  
  
  CONCLUSIONS
  A one-compartment model with first-order absorption and elimination adequately described the PK of golimumab following subcutaneous administrations in patients with AS. Body weight and anti-golimumab antibody status were found to significantly influence golimumab clearance. When a patient does not respond to the prescribed golimumab therapy, the possibility of the development of antibodies to golimumab has to be considered.
authors.affiliation: Centocor Research and Development Inc, Malvern, PA, USA.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Vu
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.forename: D
authors.initials: D
authors.lastname: Baker
authors.forename: B
authors.initials: B
authors.lastname: Hsu
authors.forename: C
authors.initials: C
authors.lastname: Pendley
authors.forename: C
authors.initials: C
authors.lastname: Wagner
authors.forename: H M
authors.initials: HM
authors.lastname: Davis
authors.forename: H
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics*; D001835:Body Weight; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D013167:Spondylitis, Ankylosing / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; C529000:golimumab