Yitong Wang1,2, Bingfeng Xu3,4, Lixia Zhu5, Kun Lou5, Yingli Chen6, Xia Zhao7, Qian Wang1, Ling Xu8, Xiaohui Guo9, Linong Ji6, Yimin Cui10, Yi Fang11. 1. Department of Pharmacy, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China. 2. Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, 100191, China. 3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, 221004, China. 4. Anhui Fuyang Pharmaceutical Group Co., Ltd., Anhui, 236000, China. 5. Clinical Medicine Department, CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Hebei, 050035, China. 6. Department of Endocrinology, Peking University People's Hospital, Beijing, 100044, China. 7. Department of Pharmacy, Peking University First Hospital, No. 8 XiShiKu Street, Xi Cheng District, Beijing, 100034, China. 8. Shanghai University of Chinese Medicine, Shanghai, 201203, China. 9. Department of Endocrinology, Peking University First Hospital, Beijing, 100034, China. 10. Department of Pharmacy, Peking University First Hospital, No. 8 XiShiKu Street, Xi Cheng District, Beijing, 100034, China. cuiymzy@126.com. 11. Department of Pharmacy, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China. phaseistudy@163.com.
Abstract
BACKGROUND AND OBJECTIVES:Recombinant glucagon-like peptide-1 receptor agonist (rE-4) is a glucagon-like peptide-1 receptor agonist, which has the same amino acid sequence to exenatide, except for the C-terminal deamidated. This study assessed the pharmacokinetics and preliminary pharmacodynamics of rE-4, following single and multiple subcutaneous injections in Chinese patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: In the randomized, open-label study, Chinese patients with T2DM (n = 36) were randomly assigned to three groups of rE-4 (n = 12), rE-4 with metformin (n = 12) and exenatide (n = 12, as the control group) for 12 weeks. rE-4 and exenatide were administered by subcutaneous injection in the abdomen, and metformin was given by oral administration. Patients received rE-4 or exenatide 5 μg twice a day for the first 4 weeks and adjusted the dose of rE-4 or exenatide to 10 μg twice a day at day 29 for the following 8 weeks, if their glycated albumin (GA) values were still greater than 17%. We evaluated pharmacokinetic parameters of rE-4 and exenatide, fasting plasma glucose (FPG), 2-h postprandial blood glucose (PG2 h), glycosylated hemoglobin (HbA1c) and body weight at designated time points. RESULTS:Thirty-six patients were enrolled, and 29 subjects finished the study. rE-4 was absorbed quickly with a median peak-reaching time (t max) of 0.8-1.5 h and eliminated rapidly with a median terminal half-life (t 1/2z) of 1.6-1.9 h. The exposure of rE-4 increased in an approximately dose-proportional method without accumulation. rE-4 10 μg twice a day could reduce FPG (~2.29 mmol/L), PG2 h (~6.00 mmol/L), HbA1c (~1.19%) and body weight (~0.48 kg) from baseline to 12 weeks, with no statistical significance compared with exenatide (FPG: ~1.88 mmol/L; PG2 h: ~6.66 mmol/L; HbA1c: ~1.13%; body weight: ~0.47 kg) and rE-4 with metformin (FPG: ~2.33 mmol/L; PG2 h: ~6.51 mmol/L; HbA1c: ~0.84%; body weight: ~1.16 kg) (p > 0.05). CONCLUSIONS:rE-4 twice a day has a pharmacokinetic profile similar to exenatide and rE-4 with metformin after single and multiple doses in Chinese patients with T2DM. Also, rE-4 could improve glycemic control effectively. CLINICALTRIALS. GOV IDENTIFIER: NCT01342042.
RCT Entities:
BACKGROUND AND OBJECTIVES: Recombinant glucagon-like peptide-1 receptor agonist (rE-4) is a glucagon-like peptide-1 receptor agonist, which has the same amino acid sequence to exenatide, except for the C-terminal deamidated. This study assessed the pharmacokinetics and preliminary pharmacodynamics of rE-4, following single and multiple subcutaneous injections in Chinese patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: In the randomized, open-label study, Chinese patients with T2DM (n = 36) were randomly assigned to three groups of rE-4 (n = 12), rE-4 with metformin (n = 12) and exenatide (n = 12, as the control group) for 12 weeks. rE-4 and exenatide were administered by subcutaneous injection in the abdomen, and metformin was given by oral administration. Patients received rE-4 or exenatide 5 μg twice a day for the first 4 weeks and adjusted the dose of rE-4 or exenatide to 10 μg twice a day at day 29 for the following 8 weeks, if their glycated albumin (GA) values were still greater than 17%. We evaluated pharmacokinetic parameters of rE-4 and exenatide, fasting plasma glucose (FPG), 2-h postprandial blood glucose (PG2 h), glycosylated hemoglobin (HbA1c) and body weight at designated time points. RESULTS: Thirty-six patients were enrolled, and 29 subjects finished the study. rE-4 was absorbed quickly with a median peak-reaching time (t max) of 0.8-1.5 h and eliminated rapidly with a median terminal half-life (t 1/2z) of 1.6-1.9 h. The exposure of rE-4 increased in an approximately dose-proportional method without accumulation. rE-4 10 μg twice a day could reduce FPG (~2.29 mmol/L), PG2 h (~6.00 mmol/L), HbA1c (~1.19%) and body weight (~0.48 kg) from baseline to 12 weeks, with no statistical significance compared with exenatide (FPG: ~1.88 mmol/L; PG2 h: ~6.66 mmol/L; HbA1c: ~1.13%; body weight: ~0.47 kg) and rE-4 with metformin (FPG: ~2.33 mmol/L; PG2 h: ~6.51 mmol/L; HbA1c: ~0.84%; body weight: ~1.16 kg) (p > 0.05). CONCLUSIONS:rE-4 twice a day has a pharmacokinetic profile similar to exenatide and rE-4 with metformin after single and multiple doses in Chinese patients with T2DM. Also, rE-4 could improve glycemic control effectively. CLINICALTRIALS. GOV IDENTIFIER: NCT01342042.
Authors: Ralph A DeFronzo; Robert E Ratner; Jenny Han; Dennis D Kim; Mark S Fineman; Alain D Baron Journal: Diabetes Care Date: 2005-05 Impact factor: 19.112
Authors: Orville G Kolterman; Dennis D Kim; Larry Shen; James A Ruggles; Loretta L Nielsen; Mark S Fineman; Alain D Baron Journal: Am J Health Syst Pharm Date: 2005-01-15 Impact factor: 2.637
Authors: Robert J Heine; Luc F Van Gaal; Don Johns; Michael J Mihm; Mario H Widel; Robert G Brodows Journal: Ann Intern Med Date: 2005-10-18 Impact factor: 25.391
Authors: Anthony H Barnett; Jude Burger; Don Johns; Robert Brodows; David M Kendall; Anthony Roberts; Michael E Trautmann Journal: Clin Ther Date: 2007-11 Impact factor: 3.393