Safety, Pharmacokinetics, and Pharmacodynamics of Globalagliatin, a Glucokinase Activator, in Chinese Patients with Type
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ORIGINAL RESEARCH ARTICLE
Safety, Pharmacokinetics, and Pharmacodynamics of Globalagliatin, a Glucokinase Activator, in Chinese Patients with Type 2 Diabetes Mellitus: A Randomized, Phase Ib, 28‑day Ascending Dose Study 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 Zheng1 · Tao Yang1 Accepted: 18 September 2020 © Springer Nature Switzerland AG 2020
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 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
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