Colorado Center for Bone Health, (Director), Lakewood, CO, USA.
Radius Health, Inc., (Clinical Pharmacology), Boston, MA, USA.
Clin Drug Investig. 2021 Mar;41(3):277-285. doi: 10.1007/s40261-021-01008-7. Epub 2021 Feb 27.
Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers.
In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50-85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety.
All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was - 1.32, and mean lumbar spine T-score was - 1.98. On Day 1, the median time to reach maximum concentration (T) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (C) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale).
Subjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS.
NCT04366726, Date of registration 04/29/2020, retrospectively registered.
阿巴洛肽是一种治疗骨质疏松症的合成代谢药物，通过皮下（SC）注射给药，可增加绝经后骨质疏松症妇女的骨密度（BMD）并降低骨折风险。阿巴洛肽固态微结构透皮系统[阿巴洛肽-sMTS（Kindeva，明尼苏达州圣保罗，美国）]，通过皮内给药，正在开发中，为阿巴洛肽的给药提供一种替代方法。本研究的目的是基于药代动力学和药效学标志物，评估受试者自我给药阿巴洛肽-sMTS 的能力。
在这项单臂、开放标签、1b 期研究中，22 名年龄在 50-85 岁、骨密度低的绝经后健康女性接受培训，每天一次在大腿上自我皮下注射阿巴洛肽-sMTS300μg，持续 5 分钟，共 29 天。主要终点是阿巴洛肽的全身暴露。次要终点包括血清 I 型前胶原 N 端前肽（s-PINP）自基线的百分比变化、患者体验和安全性。
所有 22 名受试者均完成了研究。基线时，平均年龄为 65.2 岁，平均全髋 T 评分-1.32，平均腰椎 T 评分-1.98。在第 1 天，阿巴洛肽-sMTS 达到最大浓度（T）的中位时间为 0.33 小时，几何平均值（CV%）最大浓度（C）和从 0 到最后可量化浓度的浓度时间曲线下面积（AUC）分别为 447（38.0）pg/mL 和 678（45.3）pg·h/mL；第 15 天和第 29 天的药代动力学特征相似。第 15 天和第 29 天，s-PINP 的中位百分比变化分别为 45.4%和 64.4%。最常见的不良事件（AE）是注射部位红斑、疼痛和肿胀，大多为轻度或中度。没有 AE 导致研究药物停药，也没有报告严重的 AE。首次应用时自我给药的成功率为 99.7%，受试者接受度较高（5 分制 Likert 量表约为 4.5 分）。
受试者成功自我皮下注射了阿巴洛肽-sMTS，在 29 天内提供了一致的药代动力学特征，并产生了与阿巴洛肽-SC 关键性试验中观察到的自基线 s-PINP 增加相似的作用。观察到的患者体验以及临床数据支持继续开发阿巴洛肽-sMTS。
NCT04366726，注册日期 2020 年 4 月 29 日，回顾性注册。
