Xu Zhenhua, Vu Thuy, Lee Howard, Hu Chuanpu, Ling Jie, Yan Hong, Baker Daniel, Beutler Anna, Pendley Charles, Wagner Carrie, Davis Hugh M, Zhou Honghui
Centocor Research and Development, Malvern, Pennsylvania 19355, USA.
J Clin Pharmacol. 2009 Sep;49(9):1056-70. doi: 10.1177/0091270009339192. Epub 2009 Jul 17.
The population pharmacokinetics of subcutaneously administered golimumab (50 mg or 100 mg every 4 weeks) were characterized in patients with active psoriatic arthritis (PsA) in GO-REVEAL, a randomized, double-blind, placebo-controlled, phase 3 study. A total of 2029 serum golimumab concentrations from 337 patients were analyzed using NONMEM. A 1-compartment pharmacokinetic model with first-order absorption and elimination was chosen to describe the observed concentration-time data. For a patient of standard weight (70 kg), the population estimates (typical value +/- standard error) for golimumab pharmacokinetic parameters were as follows: apparent clearance = 1.38 +/- 0.04 L/d, apparent volume of distribution = 24.9 +/- 1.04 L, and absorption rate constant = 0.908 +/- 0.121 per day. The between-subject variability was 37.6% in apparent clearance and 37.9% in apparent volume of distribution. Body weight, antibody-to-golimumab status, baseline C-reactive protein level, and smoking status were identified as significant covariates on apparent clearance. Body weight was also a significant covariate on apparent volume of distribution. None of the concomitant medications examined (methotrexate, corticosteroids, and nonsteroidal anti-inflammatory drugs) were significant covariates on apparent clearance, although the median trough golimumab concentration in patients receiving methotrexate was higher than for those not receiving methotrexate. These significant covariates account for part of the variability in systemic exposure to golimumab observed in patients with PsA.
在一项随机、双盲、安慰剂对照的3期研究GO-REVEAL中，对皮下注射戈利木单抗（每4周50毫克或100毫克）在活动性银屑病关节炎（PsA）患者中的群体药代动力学进行了研究。使用NONMEM分析了337例患者的总共2029份血清戈利木单抗浓度。选择具有一级吸收和消除的单室药代动力学模型来描述观察到的浓度-时间数据。对于标准体重（70千克）的患者，戈利木单抗药代动力学参数的群体估计值（典型值±标准误差）如下：表观清除率 = 1.38 ± 0.04升/天，表观分布容积 = 24.9 ± 1.04升，吸收速率常数 = 0.908 ± 0.121/天。表观清除率的个体间变异性为37.6%，表观分布容积的个体间变异性为37.9%。体重、抗戈利木单抗状态、基线C反应蛋白水平和吸烟状态被确定为表观清除率的显著协变量。体重也是表观分布容积的显著协变量。尽管接受甲氨蝶呤治疗的患者戈利木单抗的中位谷浓度高于未接受甲氨蝶呤治疗的患者，但所检查的任何合并用药（甲氨蝶呤、皮质类固醇和非甾体抗炎药）均不是表观清除率的显著协变量。这些显著协变量解释了PsA患者中观察到的戈利木单抗全身暴露变异性的一部分。
