title: Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp.
abstract: OBJECTIVE
  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.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden. Hans.ericsson@astrazeneca.com
authors.forename: Hans
authors.initials: H
authors.lastname: Ericsson
authors.forename: Daniel
authors.initials: D
authors.lastname: Röshammar
authors.forename: Maria
authors.initials: M
authors.lastname: Wollbratt
authors.forename: Maria
authors.initials: M
authors.lastname: Heijer
authors.forename: Maria
authors.initials: M
authors.lastname: Persson
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueda
authors.forename: Maria
authors.initials: M
authors.lastname: Leonsson-Zachrisson
authors.forename: Ensio
authors.initials: E
authors.lastname: Norjavaara
mesh_terms: D000284:Administration, Oral; D000328:Adult; D044466:Asian People; D001384:Azetidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005941:Glucokinase / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D014481:United States; D055815:Young Adult
chemical_list: C576407:AZD1656; D001384:Azetidines; D015415:Biomarkers; D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D011719:Pyrazines; D005941:Glucokinase