Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

Abstract

BACKGROUND HMS5552, a novel fourth-generation glucokinase (GK) activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HMS5552 during its first-in-human exposure. METHODS Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg), ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints. RESULTS HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0-t) and maximum plasma concentration (Cmax). Slopes estimated by linear regression for AUC0-t and Cmax were ~1.0 (0.932 and 0.933, respectively). Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (%) and mean glucose area under effect curve 0-4 hours change from baseline (%) (P<0.001). Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo). All adverse events were mild in intensity and resolved without any treatment. CONCLUSION This first-in-human single ascending dose study provided predicted PK of HMS5552 with dose-proportional increases in AUC0-t and Cmax, as well as dose-related glucose-lowering effects over the range of 5-50 mg in healthy subjects. HMS5552 at doses up to 50 mg in healthy subjects was safe and well-tolerated.

DOI: 10.2147/DDDT.S105021

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@inproceedings{Xu2016SafetyTP, title={Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study}, author={Hongrong Xu and Lei Sheng and Weili Chen and Fei Yuan and Mengjie Yang and Hui Li and Xuening Li and John D. Choi and Guiyu Zhao and Tianxin Hu and Yongguo Li and Yi Zhang and Li Chen}, booktitle={Drug design, development and therapy}, year={2016} }