Population pharmacokinetics of golimumab in patients with ankylosing spondylitis:
impact of body weight and immunogenicity.
Author(s): Xu ZH, Lee H, Vu T, Hu C, Yan H, Baker D, Hsu B, Pendley C, Wagner C, Davis HM,
Zhou H.
Affiliation(s): Centocor Research and Development Inc, Malvern, PA, USA.
Publication date & source: 2010, Int J Clin Pharmacol Ther. , 48(9):596-607
AIMS: 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.
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