Zhu Y W, Mendelsohn A, Pendley C, Davis H M, Zhou H
Pharmacokinetics, Modeling and Simulation, Biologics Clinical Pharmacology, Centocor Research & Development, Inc., 200 Great Valley Parkway, Malvern, PA 19355, USA.
Int J Clin Pharmacol Ther. 2010 Dec;48(12):830-46. doi: 10.5414/cpp48830.
To characterize the population pharmacokinetics of subcutaneous ustekinumab, a human IgG1Kappa; monoclonal antibody against interleukin-12/23p40, using data from a randomized, double-blind, placebo-controlled Phase II study in patients with active psoriatic arthritis (PsA).
A total of 786 quantifiable serum ustekinumab concentrations from 130 patients were analyzed using a nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was selected as the structural model.
The population typical mean (percent relative standard error (%RSE)) values for apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) obtained from the final covariate model were 0.465 l × day-1 (5.1%), 14.3 l (4.4%), and 0.427 day-1 (3.9%), respectively. The between-subject variability in CL/F, V/F, and ka were 53.9%, 42.3%, and 82.4%, respectively. Patient body weight and antibody-to-ustekinumab status were significant covariates affecting the CL/F and/or V/F of ustekinumab. None of the other factors evaluated, such as age, sex, race, baseline disease characteristics, concomitant methotrexate or nonsteroidal anti-inflammatory drugs, and past use of immunosuppressives, biologics, systemic corticosteroids, or disease-modifying antirheumatic drugs, were found to have significant effects on the pharmacokinetics of ustekinumab.
The pharmacokinetics of ustekinumab in patients with PsA are comparable to those in patients with moderate-to-severe plaque psoriasis which was previously investigated.
利用一项针对活动性银屑病关节炎（PsA）患者的随机、双盲、安慰剂对照II期研究的数据，对皮下注射优特克单抗（一种抗白细胞介素-12/23 p40的人IgG1κ单克隆抗体）的群体药代动力学进行表征。
采用非线性混合效应建模方法分析了130例患者的786个可量化血清优特克单抗浓度。选择具有一级吸收和消除的单室模型作为结构模型。
从最终协变量模型获得的表观清除率（CL/F）、表观分布容积（V/F）和吸收速率常数（ka）的群体典型均值（相对标准误差百分比（%RSE））分别为0.465 l×天-1（5.1%）、14.3 l（4.4%）和0.427天-1（3.9%）。CL/F、V/F和ka的个体间变异性分别为53.9%、42.3%和82.4%。患者体重和抗优特克单抗状态是影响优特克单抗CL/F和/或V/F的显著协变量。未发现评估的其他因素，如年龄、性别、种族、基线疾病特征、同时使用甲氨蝶呤或非甾体抗炎药，以及既往使用免疫抑制剂、生物制剂、全身用皮质类固醇或改善病情的抗风湿药物，对优特克单抗的药代动力学有显著影响。
PsA患者中优特克单抗的药代动力学与先前研究的中度至重度斑块状银屑病患者的药代动力学相当。
