Xu Z H, Lee H, Vu T, Hu C, Yan H, Baker D, Hsu B, Pendley C, Wagner C, Davis H M, Zhou H
Centocor Research and Development Inc, Malvern, PA, USA.
Int J Clin Pharmacol Ther. 2010 Sep;48(9):596-607. doi: 10.5414/cpp48596.
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.
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.
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.
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.
建立皮下注射戈利木单抗（一种人抗肿瘤坏死因子单克隆抗体）在强直性脊柱炎（AS）患者中的群体药代动力学（PK）模型，估计典型的固定和随机群体PK参数，并确定影响戈利木单抗药代动力学的显著协变量。
使用非线性混合效应建模方法分析了戈利木单抗（每4周50或100 mg）随机、双盲、安慰剂对照III期试验至第24周的血清浓度数据。评估了潜在协变量对戈利木单抗的影响。
选择具有一级吸收和消除的单室PK模型来描述AS患者中观察到的戈利木单抗浓度-时间数据。从最终模型获得的典型70 kg患者的群体估计值为：表观全身清除率（CL/F），1.41 l/天（95%置信区间（CI）：1.31 - 1.51）和表观分布容积（V/F），22.6 L（95%CI：20.7 - 24.4）。一级吸收速率常数（Ka）估计为1.01天-1（95%CI：0.760 - 1.46）。CL/F、V/F和Ka的个体间变异性分别为35.2%、38.6%和78.6%。体重是最显著的协变量，影响CL/F和V/F。抗戈利木单抗状态、基线C反应蛋白水平和性别也被确定为CL/F的显著协变量。
具有一级吸收和消除的单室模型充分描述了AS患者皮下注射后戈利木单抗的PK。发现体重和抗戈利木单抗抗体状态显著影响戈利木单抗清除率。当患者对规定的戈利木单抗治疗无反应时，必须考虑产生抗戈利木单抗抗体的可能性。
