NDLI: Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ericsson, Hans Röshammar, Daniel Wollbratt, Maria Heijer, Maria Persson, Maria Ueda, Shinya Leonsson-Zachrisson, Maria Norjavaara, Ensio
Spatial Coverage	United States
Description	Country affiliation: Sweden Author Affiliation: Ericsson H ( AstraZeneca R&D, Mölndal, Sweden. Hans.ericsson@astrazeneca.com)
Abstract	OBJECTIVES: AZD1656 is a novel glucokinase activator with a postulated dual mechanism of action by activating glucokinase in both the pancreas and the liver, and with the potential to deliver effective glucose-lowering in Type 2 diabetes mellitus. Here, we present the tolerability, pharmacokinetics and pharmacodynamics of AZD1656 in two single-blind, randomized, placebo-controlled studies, one with Western and the other with Japanese healthy adult male subjects. METHODS: Both studies evaluated oral single ascending doses of AZD1656 of up to 180 mg, administered during euglycemic clamp conditions to explore a wide dose range without risking hypoglycemia. Safety, pharmacokinetics and effects on serum insulin and glucose infusion rate were assessed. A population pharmacokinetics analysis was also conducted. RESULTS: AZD1656 was well tolerated in single doses up to 180 mg in both populations. AZD1656 was rapidly absorbed, and a dose-proportional increase in total exposure was observed for AZD1656 and the equipotent metabolite, AZD5658. Taking differences in body weight into account, there were no differences in pharmacokinetic parameters between Western and Japanese subjects. A dose-dependent blood glucose lowering effect was indirectly demonstrated by the increased glucose infusion rate required to maintain euglycemia, which was of similar magnitude in both populations. Dose-dependent increases in insulin secretion were also observed. CONCLUSIONS: No safety concerns were raised. AZD1656 displayed uncomplicated pharmacokinetics and dose-dependent pharmacodynamics effects were observed. The results suggest no ethnic differences in AZD1656 tolerability, pharmacokinetics or pharmacodynamics.
File Format	HTM / HTML
ISSN	09461965
Issue Number	11
Volume Number	50
Journal	Int. Journal of Clinical Pharmacology and Therapeutics
Language	English
Publisher	Dustri-Verlag
Publisher Date	2012-11-01
Publisher Place	Germany
Access Restriction	Subscribed
Subject Keyword	Discipline Pharmacology Azetidines Administration & Dosage Pharmacokinetics Blood Glucose Drug Effects Enzyme Activators Glucokinase Metabolism Glucose Clamp Technique Hypoglycemic Agents Pyrazines Administration, Oral Adult Asian Continental Ancestry Group Adverse Effects Biological Markers Blood Dose-response Relationship, Drug Enzyme Activation Humans Insulin Male Middle Aged Models, Biological Single-blind Method United States Young Adult Comparative Study Journal Article Randomized Controlled Trial Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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