Liu Yani, Yang Chunxiao, Li Zhongfang, Zhou Jiali, Lv Yongning, Zhang Yu, Zeng Fandian, Shi Shaojun
Clinical Research Organization for Pharmaceutical Products, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Clinical Research Organization for Pharmaceutical Products, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Clinical Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Clin Ther. 2014 Jun 1;36(6):940-52. doi: 10.1016/j.clinthera.2014.03.015. Epub 2014 Apr 29.
The recombinant human parathyroid hormone (1-34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China.
The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1-34) after single and multiple subcutaneous doses in healthy Chinese subjects.
Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1-34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1-34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1-34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1-34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters.
Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1-34) was well tolerated during the investigated single (10-60 μg) and multiple (10-20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1-34), the drug was rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t½ of 47.2 to 60.6 minutes. The mean Cmax, AUC0-t, and AUC0-∞ increased in proportion to the doses, whereas the t½, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-μg and 20-μg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels.
All rhPTH(1-34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.
重组人甲状旁腺激素（1-34）（rhPTH[1-34]）特立帕肽是美国食品药品监督管理局批准的首个用于治疗男性和女性骨质疏松症的促合成药物。本研究旨在为中国一种特立帕肽生物类似药的上市许可提供支持。
本研究的主要目的是评估健康中国受试者单次和多次皮下注射rhPTH（1-34）后的安全性、耐受性、药代动力学和药效学参数。
进行了两项开放标签、随机、单中心、剂量递增研究。在研究1中，受试者被随机分配接受单次剂量的rhPTH（1-34）（10、20、30、40、50或60μg）或多次剂量的rhPTH（1-34）（10和20μg，连续7天每日一次），以确定安全性概况和耐受性，这通过观察到的不良事件的发生率、强度和严重程度来反映。在研究2中，皮下注射单次剂量的rhPTH（1-34）（10、20或40μg）和多次剂量的rhPTH（1-34）（20μg），以研究药代动力学和药效学参数。
42名受试者完成了研究1，30名受试者完成了研究2。在研究的单次（10 - 60μg）和多次（连续7天每日一次10 - 20μg）剂量范围内，rhPTH（1-34）耐受性良好。最常报告的不良事件是注射部位红斑和胃肠道反应。单次和多次皮下注射rhPTH（1-34）后，药物吸收迅速，达峰时间（Tmax）为20至30分钟，从血浆中清除也迅速，半衰期（t½）为47.2至60.6分钟。平均血药浓度峰值（Cmax）、药时曲线下面积（AUC0-t）和药时曲线下面积至无穷大（AUC0-∞）与剂量成比例增加，而t½、总清除率和Tmax值与给药剂量无关。除了10μg和减20μg单次剂量组的Tmax外，药代动力学参数在性别上无显著差异。与基线水平相比，血清钙和磷水平未观察到显著变化或剂量相关的显著影响。
在所研究的人群中，所有rhPTH（1-34）剂量似乎耐受性良好。在所研究的剂量范围内呈现线性药代动力学特征。中国临床试验注册中心标识符：ChiCTR-ONC-12002874。
