静脉注射托珠单抗治疗巨细胞动脉炎：一项 Ib 期剂量范围药代动力学桥接研究。
Intravenous tocilizumab for the treatment of giant cell arteritis: a phase Ib dose-ranging pharmacokinetic bridging study.
机构信息
Department of Clinical Pharmacology, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland.
F. Hoffmann-La Roche Ltd, Welwyn Garden City, UK.
出版信息
Arthritis Res Ther. 2022 Jun 4;24(1):133. doi: 10.1186/s13075-022-02815-9.
BACKGROUND
Subcutaneous tocilizumab (TCZ SC) is approved globally for giant cell arteritis (GCA). This phase Ib study investigated the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of intravenous (IV) TCZ 6 and 7 mg/kg in patients with GCA. This study explored an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA).
METHODS
Patients with GCA who had received ≥ 5 doses of TCZ IV 8 mg/kg Q4W and achieved remission were enrolled. Patients received 5 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, 5 doses of 6 mg/kg Q4W in period 2. Pharmacokinetic endpoints were maximum concentration (C), minimum concentration (C), area under the curve over a dosing interval (AUC), and mean concentration (C) of TCZ after the last dose of each period. Other endpoints included pharmacodynamic markers, safety, and exploratory efficacy.
RESULTS
In 24 patients, the median (range) age was 65.5 (57-90) years, and 62.5% were female. TCZ exposures (C and AUC) were 11.2% and 20.0% lower at the 6- than 7-mg/kg dose. The mean interleukin 6 (IL-6) serum concentrations were elevated at baseline and remained elevated, with slightly higher concentrations in period 1 than in period 2. The mean serum soluble IL-6 receptor concentrations were elevated at baseline and comparable between the 2 doses at steady state. C-reactive protein levels and most erythrocyte sedimentation rates were within normal ranges throughout the study. Overall, 22 patients (91.7%) had ≥ 1 adverse event, and 4 (16.7%) had a serious adverse event. No patients experienced a GCA flare, and all remained in remission throughout the study.
CONCLUSIONS
Both doses of TCZ IV Q4W were generally well tolerated in patients with GCA. The C and C achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those in patients with RA treated with 8 mg/kg IV Q4W, and C was within the range observed in patients with GCA treated with SC dosing every week or every 2 weeks.
TRIAL REGISTRATION
ClinicalTrials.gov , NCT03923738.
背景
皮下注射托珠单抗（TCZ SC）已在全球范围内获批用于巨细胞动脉炎（GCA）。这项 Ib 期研究旨在探究 GCA 患者中静脉注射（IV）TCZ 6 毫克/千克和 7 毫克/千克的药代动力学、药效学、安全性和探索性疗效。本研究旨在探索一种 IV 剂量，使其暴露水平最低，处于 TCZ SC 剂量治疗 GCA 时达到的有效谷浓度范围内，且不超过在类风湿关节炎（RA）中耐受良好的每 4 周（Q4W）8 毫克/千克 IV 的暴露量。
方法
本研究纳入了已接受至少 5 剂 TCZ IV 8 毫克/千克 Q4W 且已缓解的 GCA 患者。患者在第 1 期间接受 5 剂 TCZ IV 7 毫克/千克 Q4W，若仍处于缓解期，则在第 2 期间接受 5 剂 6 毫克/千克 Q4W。药代动力学终点包括 TCZ 的最大浓度（C）、最小浓度（C）、给药间隔内的曲线下面积（AUC）和最后一剂后的平均浓度（C）。其他终点包括药效学标志物、安全性和探索性疗效。
结果
在 24 名患者中，中位（范围）年龄为 65.5（57-90）岁，62.5%为女性。与 7 毫克/千克剂量相比，6 毫克/千克剂量的 TCZ 暴露（C 和 AUC）分别低 11.2%和 20.0%。基线时血清白细胞介素 6（IL-6）浓度升高，且持续升高，第 1 期间的浓度略高于第 2 期间。稳态时血清可溶性 IL-6 受体浓度升高，两种剂量之间无差异。整个研究过程中，C-反应蛋白水平和大多数红细胞沉降率均在正常范围内。总体而言，22 名患者（91.7%）发生了≥1 次不良事件，4 名患者（16.7%）发生了严重不良事件。没有患者出现 GCA 发作，所有患者在整个研究期间均保持缓解。
结论
两种剂量的 TCZ IV Q4W 通常在 GCA 患者中耐受良好。GCA 患者接受 6 毫克/千克 IV Q4W 后的 C 和 C 与接受 8 毫克/千克 IV Q4W 的 RA 患者相似，C 处于每周或每 2 周接受 SC 剂量治疗的 GCA 患者观察到的范围内。
临床试验注册
ClinicalTrials.gov ，NCT03923738。
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