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

ABSTRACT: 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.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.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.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.

SUBMITTER: Xu H

PROVIDER: S-EPMC4869670 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Xu Hongrong H Sheng Lei L Chen Weili W Yuan Fei F Yang Mengjie M Li Hui H Li Xuening X Choi John J Zhao Guiyu G Hu Tianxin T Li Yongguo Y Zhang Yi Y Chen Li L

Drug design, development and therapy 20160509

<h4>Background</h4>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.<h4>Methods</h4>Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg), ten subjects were random ...[more]

PMID: 27274195

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Dataset Information

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

Publications

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

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