{"title":"HLX14与参考药物地诺单抗在健康男性中的药代动力学、药效学、安全性和免疫原性:随机 I 期研究","authors":"Nanyang Li, Nannan Chu, Leilei Zhu, Xiaojie Wu, Qiong Wei, Jiahui Wang, Xuhui Hu, Haoyu Yu, Qingyu Wang, Wei'an Yuan, Kai Huang, Jing Zhang","doi":"10.1111/cts.70089","DOIUrl":null,"url":null,"abstract":"<p>Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration–time curve from time 0 to the last concentration-quantifiable time <i>t</i> (AUC<sub>0–t</sub>), maximum serum drug concentration (<i>C</i><sub>max</sub>), and area under the serum drug concentration–time curve from time 0 to infinity (AUC<sub>0–inf</sub>). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC<sub>0–<i>t</i></sub>, <i>C</i><sub>max</sub>, and AUC<sub>0–inf</sub> between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80–1.25 (AUC<sub>0–<i>t</i></sub>, 0.91–1.13; <i>C</i><sub>max</sub>, 0.91–1.13; AUC<sub>0–inf</sub>, 0.91–1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70089","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study\",\"authors\":\"Nanyang Li, Nannan Chu, Leilei Zhu, Xiaojie Wu, Qiong Wei, Jiahui Wang, Xuhui Hu, Haoyu Yu, Qingyu Wang, Wei'an Yuan, Kai Huang, Jing Zhang\",\"doi\":\"10.1111/cts.70089\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration–time curve from time 0 to the last concentration-quantifiable time <i>t</i> (AUC<sub>0–t</sub>), maximum serum drug concentration (<i>C</i><sub>max</sub>), and area under the serum drug concentration–time curve from time 0 to infinity (AUC<sub>0–inf</sub>). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC<sub>0–<i>t</i></sub>, <i>C</i><sub>max</sub>, and AUC<sub>0–inf</sub> between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80–1.25 (AUC<sub>0–<i>t</i></sub>, 0.91–1.13; <i>C</i><sub>max</sub>, 0.91–1.13; AUC<sub>0–inf</sub>, 0.91–1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.</p>\",\"PeriodicalId\":50610,\"journal\":{\"name\":\"Cts-Clinical and Translational Science\",\"volume\":\"17 12\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-12-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70089\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cts-Clinical and Translational Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cts.70089\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cts-Clinical and Translational Science","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cts.70089","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study
Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration–time curve from time 0 to the last concentration-quantifiable time t (AUC0–t), maximum serum drug concentration (Cmax), and area under the serum drug concentration–time curve from time 0 to infinity (AUC0–inf). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC0–t, Cmax, and AUC0–inf between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80–1.25 (AUC0–t, 0.91–1.13; Cmax, 0.91–1.13; AUC0–inf, 0.91–1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.
期刊介绍:
Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.