Zheng Yanan, Abuqayyas Lubna, Megally Ayman, Fuhr Rainard, Sałapa Kinga, Downie John, Colice Gene
Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, South San Francisco, CA, USA.
Clinical Pharmacology Modeling and Simulation, Amgen, Cambridge, MA, USA.
Clin Ther. 2021 Jan;43(1):142-155.e5. doi: 10.1016/j.clinthera.2020.11.014. Epub 2020 Dec 27.
Tezepelumab is an anti-thymic stromal lymphopoietin monoclonal antibody therapeutic in development for patients with severe, uncontrolled asthma. In ongoing Phase III studies, tezepelumab is administered via subcutaneous (SC) injections using a vial-and-syringe (V-S). This study compared the pharmacokinetic (PK) parameters, safety, and tolerability of tezepelumab administered subcutaneously via V-S versus via an accessorized prefilled syringe (APFS) or autoinjector (AI).
This single-center, randomized, open-label, parallel-group study was conducted in healthy volunteers aged 18-65 years. Participants, stratified according to weight (50 to <70 kg, 70 to <80 kg, or 80-90 kg), were randomized evenly to 9 groups representing injections to the abdomen, thigh, or upper arm via V-S, APFS, or AI. Tezepelumab PK parameters over 113 days were evaluated after a single 210-mg SC dose. The primary end points were comparison of C and AUC between device groups. Further PK parameters, immunogenicity, safety (including injection site reactions [ISRs] and injection site pain [visual analog scale]) were also assessed.
A total of 315 adults were randomized to treatment. Geometric mean ratios for comparisons between device groups of C, AUC, and AUC were close to 1, with 90% CIs all within the range of 0.8-1.25, meeting bioequivalence criteria. PK variables were also similar between devices across injection sites and weight categories. Across devices, thigh injection resulted in slightly higher exposure than upper arm injection, and abdomen injection resulted in exposure similar to or slightly lower than thigh injection; however, these differences were not clinically meaningful. Treatment-emergent anti-tezepelumab antibodies were present in 3 (2.9%), 1 (1.0%), and 0 participants in the V-S, APFS, and AI groups, respectively. Treatment-related adverse events were reported in 15.0% of participants overall (V-S, 10.7%; APFS, 18.1%; AI, 16.0%), including ISRs in 1 (1.0%), 3 (2.9%), and 3 (2.8%) participants in the V-S, APFS, and AI groups. Median visual analog scale pain score (0-100 mm scale) was 2 mm immediately after injection and was 0 mm at 30 min for all groups.
Tezepelumab PK parameters after a single 210-mg SC dose were comparable when administered via V-S, APFS, or AI. In all groups, immunogenicity rate and injection site pain were low, and ISRs were uncommon. These findings support administration of tezepelumab via APFS or AI, in addition to V-S, providing patients and physicians with greater choice and the potential convenience of at-home use. ClinicalTrials.gov identifier: NCT03989544.
tezepelumab是一种抗胸腺基质淋巴细胞生成素单克隆抗体，正在开发用于治疗严重的、未得到控制的哮喘患者。在正在进行的III期研究中，tezepelumab通过使用小瓶和注射器（V-S）进行皮下（SC）注射给药。本研究比较了通过V-S与通过配套预填充注射器（APFS）或自动注射器（AI）皮下注射tezepelumab的药代动力学（PK）参数、安全性和耐受性。
本单中心、随机、开放标签、平行组研究在18至65岁的健康志愿者中进行。参与者根据体重（50至<70 kg、70至<80 kg或80 - 90 kg）分层，被均匀随机分为9组，分别代表通过V-S、APFS或AI注射到腹部、大腿或上臂。在单次210 mg SC剂量后，评估113天内的tezepelumab PK参数。主要终点是比较各器械组之间的C和AUC。还评估了进一步的PK参数、免疫原性、安全性（包括注射部位反应[ISR]和注射部位疼痛[视觉模拟量表]）。
共有315名成年人被随机分配接受治疗。各器械组之间C、AUC和AUC比较的几何平均比值接近1，90%置信区间均在0.8 - 1.25范围内，符合生物等效性标准。各器械在不同注射部位和体重类别之间的PK变量也相似。在所有器械中，大腿注射导致的暴露略高于上臂注射，腹部注射导致的暴露与大腿注射相似或略低于大腿注射；然而，这些差异无临床意义。V-S组、APFS组和AI组分别有3名（2.9%）、1名（1.0%）和0名参与者出现治疗中出现的抗tezepelumab抗体。总体上，15.0%的参与者报告了与治疗相关的不良事件（V-S组为10.7%；APFS组为18.1%；AI组为16.0%），包括V-S组、APFS组和AI组分别有1名（1.0%）、3名（2.9%）和三名（2.8%）参与者出现ISR。注射后立即的视觉模拟量表疼痛评分中位数（0 - 100 mm量表）为2 mm，所有组在30分钟时均为0 mm。
单次210 mg SC剂量的tezepelumab通过V-S、APFS或AI给药时，PK参数具有可比性。在所有组中，免疫原性率和注射部位疼痛较低，ISR不常见。这些发现支持除V-S外，也可通过APFS或AI给药tezepelumab，为患者和医生提供了更多选择以及在家使用的潜在便利性。ClinicalTrials.gov标识符：NCT03989544。
