Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA.
Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA.
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DOI：
10.1002/jcph.826
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发表时间：
2017-04
影响因子：
2.9
通讯作者：
Kivitz A
中科院分区：
文献类型：
--
作者：
Abdallah H;Hsu JC;Lu P;Fettner S;Zhang X;Douglass W;Bao M;Rowell L;Burmester GR;Kivitz A
Tocilizumab是一种人源化抗白细胞介素-6受体抗体，用于治疗类风湿性关节炎。对2项随机对照试验（SUMMACTA和BREVACTA）的24周双盲部分进行了药代动力学/药效学分析。SUMMACTA比较了皮下注射托珠单抗162 mg/周与静脉注射托珠单抗8 mg/kg/4周，而BREVACTA评价了皮下注射托珠单抗162 mg/2周与安慰剂。除非房室分析外，还使用了一级吸收（皮下）、线性和米氏消除的二房室群体药代动力学模型。第24周皮下给药和每2周一次给药时，观察到的平均稳态给药前托珠单抗浓度分别为40和7.4 μg/mL，静脉给药时为18 μg/mL。在群体PK模型中，体重是影响清除率和分布容积的重要协变量。对于体重≥100 kg的患者，每周一次皮下注射托珠单抗的平均± SD群体预测给药前浓度为23.0 ± 13.5 μg/mL，每2周一次为1.0 ± 1.6 μg/mL。在> 100 kg的患者中，每2周一次皮下给药的疗效最低，反映了较低的暴露量。不建议这些患者接受每2周一次皮下注射方案。每周一次皮下给药和每4周一次静脉给药方案的药效学反应相当，每2周一次皮下给药方案的药效学反应不太明显。未观察到不良事件随托珠单抗暴露量增加而增加的趋势。该分析的结果与每周一次皮下给药方案相对于每4周一次静脉给药方案的疗效非劣效性和每2周一次皮下给药方案相对于安慰剂的优效性一致。这些结果支持托珠单抗在类风湿性关节炎患者中皮下给药的标签建议。
Tocilizumab is a humanized anti–interleukin‐6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24‐week double‐blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2‐compartment population pharmacokinetic model, with first‐order absorption (for subcutaneous) and linear and Michaelis–Menten elimination was used. Mean observed steady‐state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every‐week and every‐2‐week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population‐predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every‐2‐week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every‐2‐week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every‐week subcutaneous and every‐4‐week intravenous regimens and less pronounced with the every‐2‐week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every‐week subcutaneous regimen to the every‐4‐week intravenous regimen and the superiority of the every‐2‐week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.