Yitong Wang1,2, Chang Liu1,3, Shi Chen4, Wei Wang5, Lihou Dong6, Qian Wang1, Yan Wang1, Libo Zhao7, Yannan Zang8, Zhenwei Xie9, Yang Liu1,2, Yanjun Liu10, Haifeng Song6, Zhanguo Li4, Yi Fang11. 1. Department of Pharmacy, Peking University People's Hospital, Beijing, 100044, China. 2. Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. 3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, 221004, China. 4. Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China. 5. Department of Medicine, Shanghai Fudan-zhangjiang Bio-Pharmaceutical Co. Ltd, Shanghai, 201210, China. 6. Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, 100850, China. 7. Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China. 8. Department of Pharmacy, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China. 9. Department of Scientific Research, Peking University People's Hospital, Beijing, 100044, China. 10. Academia Sinica, Shanghai Pharmaceuticals Holding Co. Ltd, Shanghai, 200020, China. 11. Department of Pharmacy, Peking University People's Hospital, Beijing, 100044, China. phaseistudy@163.com.
Abstract
PURPOSE: T0001 was the first mutant of recombinant fusion protein of human tumor necrosis factor receptor and Fc fragment (rhTNFR:Fc) based on etanercept on a global scale. This study was carried out to investigate the pharmacokinetics (PK) and immunogenicity of T0001 in healthy Chinese volunteers. METHODS: This study was randomized, with a single ascending dose, and the first-in-human clinical trial of T0001. Healthy Chinese volunteers (n = 56; male: female = 1:1) were randomly assigned to receive a single subcutaneous (sc) injection of 10, 20, 35, 50, 65 or 75 mg of T0001. Blood samples were collected at designated time points after sc injection to assess immunogenicity and pharmacokinetics of T0001. RESULTS: During the study, no serious adverse events were observed. T0001 was slowly absorbed with a median Tmax of 84 h and slowly eliminated with a T1/2Z of 42.1-58.2 h. In the dose-exposure proportionality analysis, the estimated points for AUC0-∞ and Cmax were 0.87 with a 90% CI of 0.76-0.98 and 0.86 with a 90% CI of 0.74-0.97 respectively. The plasma concentration of free (unbound T0001) plasma TNFα and total (bound and unbound T0001) TNFα both increased significantly after the injection of T0001. Ten out of 56 volunteers (17.9%) tested positive for anti-drug antibodies (ADAs) at a low level. CONCLUSIONS: T0001 was safe and well-tolerated at doses up to 75 mg. Cmax and AUC0-∞ had an increasing tendency with dose levels, but we could not conclude that T0001 has linear PK properties in this study.
RCT Entities:
PURPOSE: T0001 was the first mutant of recombinant fusion protein of humantumornecrosis factor receptor and Fc fragment (rhTNFR:Fc) based on etanercept on a global scale. This study was carried out to investigate the pharmacokinetics (PK) and immunogenicity of T0001 in healthy Chinese volunteers. METHODS: This study was randomized, with a single ascending dose, and the first-in-human clinical trial of T0001. Healthy Chinese volunteers (n = 56; male: female = 1:1) were randomly assigned to receive a single subcutaneous (sc) injection of 10, 20, 35, 50, 65 or 75 mg of T0001. Blood samples were collected at designated time points after sc injection to assess immunogenicity and pharmacokinetics of T0001. RESULTS: During the study, no serious adverse events were observed. T0001 was slowly absorbed with a median Tmax of 84 h and slowly eliminated with a T1/2Z of 42.1-58.2 h. In the dose-exposure proportionality analysis, the estimated points for AUC0-∞ and Cmax were 0.87 with a 90% CI of 0.76-0.98 and 0.86 with a 90% CI of 0.74-0.97 respectively. The plasma concentration of free (unbound T0001) plasma TNFα and total (bound and unbound T0001) TNFα both increased significantly after the injection of T0001. Ten out of 56 volunteers (17.9%) tested positive for anti-drug antibodies (ADAs) at a low level. CONCLUSIONS: T0001 was safe and well-tolerated at doses up to 75 mg. Cmax and AUC0-∞ had an increasing tendency with dose levels, but we could not conclude that T0001 has linear PK properties in this study.
Authors: Lara Gibellini; Sara De Biasi; Elena Bianchini; Regina Bartolomeo; Antonella Fabiano; Marco Manfredini; Federica Ferrari; Giuseppe Albertini; Tommaso Trenti; Milena Nasi; Marcello Pinti; Anna Iannone; Carlo Salvarani; Andrea Cossarizza; Giovanni Pellacani Journal: PLoS One Date: 2016-12-09 Impact factor: 3.240