Shuai Zheng1, Feng Shao2, Yu Ding1, Zhenzhen Fu1, Qi Fu1, Sijia Ding2, Lijun Xie2, Juan Chen2, Sufeng Zhou2, Hongwen Zhang2, Hongwen Zhou1, Yang Chen1, Caixia Sun3, Jing Zhu3, Xuqin Zheng4, Tao Yang5. 1. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. 2. Phase I Clinical Trial Unit, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. 3. Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou, Jiangsu, China. 4. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. zhengxuqin@njmu.edu.cn. 5. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. yangt@njmu.edu.cn.
Abstract
BACKGROUND AND OBJECTIVES:Globalagliatin, a glucokinase activator, plays a vital role in glucose homeostasis. The aim of this study was to assess the safety, pharmacokinetics, and pharmacodynamics of globalagliatin in Chinese patients with type 2 diabetes. METHODS: In this dose-titration study, 24 patients were randomized (3:1 ratio) to receiveglobalagliatin or placebo. The 28-day titration was divided into two stages, each comprising 12 subjects. In stage I (low-dose), globalagliatin or placebo was administered at ascending doses of 20, 40, 80, and 120 mg once daily, increased at weekly intervals. As the treatment was well tolerated, stage II (high-dose) was initiated, with ascending doses of 80, 160, 240, and 320 mg. Safety, pharmacokinetic and pharmacodynamic analysis were conducted. RESULTS: Following once-daily titration with ascending doses of globalagliatin of 20-120 mg (stage I) and 80-320 mg (stage II) for 7 days, globalagliatin caused mildly high incidences of hypoglycemia and hypertriglyceridemia. The mean maximum plasma concentration (Cmax) of globalagliatin increased from 7.76 to 138.13 ng/mL (stage I), and 29.36 to 471.50 ng/mL (stage II), which occurred at 3-5 h post-dose. A steady state was achieved after 7 days of once-daily dosing in stage I and stage II, respectively. Mean area under the plasma-concentration curve for steady-state 24-h interval (AUC0-24) increased from 106.13 to 2461.95 ng·h/mL (stage I) and 369.71 to 9218.38 ng·h/mL (stage II). Fasting plasma glucose (FPG) decreased continuously during the titration period. Compared with the placebo, high-dose globalagliatin significantly increased the reductions in FPG, the area under the curve of 24-h glucose levels, and glycated albumin, with least-squares mean changes (relative to baseline) of - 4.08 mmol/L (95% CI - 5.05 to - 3.12) (P < 0.01), - 103.93 mmol/L (95% CI - 135.80 to - 72.06) (P < 0.01), and - 4.71% (95% CI - 6.91 to - 2.51) (P < 0.01)), respectively. High-dose globalagliatin significantly increased the Matsuda index, indicating improved insulin resistance. CONCLUSIONS:Globalagliatin was well tolerated and showed favorable pharmacokinetic profiles in Chinese patients with type 2 diabetes. High-dose globalagliatin reduced plasma glucose, and improved insulin resistance. TRIAL REGISTRATION: Clinicaltrials.gov indentifier, NCT03414892.
RCT Entities:
BACKGROUND AND OBJECTIVES:Globalagliatin, a glucokinase activator, plays a vital role in glucose homeostasis. The aim of this study was to assess the safety, pharmacokinetics, and pharmacodynamics of globalagliatin in Chinese patients with type 2 diabetes. METHODS: In this dose-titration study, 24 patients were randomized (3:1 ratio) to receive globalagliatin or placebo. The 28-day titration was divided into two stages, each comprising 12 subjects. In stage I (low-dose), globalagliatin or placebo was administered at ascending doses of 20, 40, 80, and 120 mg once daily, increased at weekly intervals. As the treatment was well tolerated, stage II (high-dose) was initiated, with ascending doses of 80, 160, 240, and 320 mg. Safety, pharmacokinetic and pharmacodynamic analysis were conducted. RESULTS: Following once-daily titration with ascending doses of globalagliatin of 20-120 mg (stage I) and 80-320 mg (stage II) for 7 days, globalagliatin caused mildly high incidences of hypoglycemia and hypertriglyceridemia. The mean maximum plasma concentration (Cmax) of globalagliatin increased from 7.76 to 138.13 ng/mL (stage I), and 29.36 to 471.50 ng/mL (stage II), which occurred at 3-5 h post-dose. A steady state was achieved after 7 days of once-daily dosing in stage I and stage II, respectively. Mean area under the plasma-concentration curve for steady-state 24-h interval (AUC0-24) increased from 106.13 to 2461.95 ng·h/mL (stage I) and 369.71 to 9218.38 ng·h/mL (stage II). Fasting plasma glucose (FPG) decreased continuously during the titration period. Compared with the placebo, high-dose globalagliatin significantly increased the reductions in FPG, the area under the curve of 24-h glucose levels, and glycated albumin, with least-squares mean changes (relative to baseline) of - 4.08 mmol/L (95% CI - 5.05 to - 3.12) (P < 0.01), - 103.93 mmol/L (95% CI - 135.80 to - 72.06) (P < 0.01), and - 4.71% (95% CI - 6.91 to - 2.51) (P < 0.01)), respectively. High-dose globalagliatin significantly increased the Matsuda index, indicating improved insulin resistance. CONCLUSIONS:Globalagliatin was well tolerated and showed favorable pharmacokinetic profiles in Chinese patients with type 2 diabetes. High-dose globalagliatin reduced plasma glucose, and improved insulin resistance. TRIAL REGISTRATION: Clinicaltrials.gov indentifier, NCT03414892.