title: The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food.
abstract: OBJECTIVE
  To investigate the pharmacodynamics, pharmacokinetics and safety of the glucokinase activator AZD6370 after 1 day of administration under fed and fasted conditions in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  This was a two-part study. In Part A, patients received a single oral dose of AZD6370 (20, 60 or 180 mg) or placebo in the fasted or fed states (both n=8). In Part B, patients (n=8) received placebo and a total dose of AZD6370 180 mg given in one, two or four divided doses. Plasma glucose, insulin and C-peptide changes versus placebo were assessed.
  
  
  RESULTS
  AZD6370 provided dose-dependent reductions in plasma glucose of up to 30% versus placebo in both fasted and fed patients (p<0.001 at 60 and 180 mg doses). Insulin secretion increased with dose, but absolute increases were relatively small in the fasted versus fed state (0-4 h). Dosing AZD6370 twice or four-times over 1 day gave a smoother 24-h glucose profile than single-dose. AZD6370 was rapidly absorbed. Pharmacokinetics of AZD6370 were dose-independent and unaffected by food. AZD6370 was generally well tolerated.
  
  
  CONCLUSIONS
  AZD6370 produced dose-dependent glucose reductions and increased glucose-stimulated insulin secretion in patients with T2DM.
authors.affiliation: AstraZeneca R&D, MöIndal, Sweden. Hans.Ericsson@astrazeneca.com
authors.forename: Hans
authors.initials: H
authors.lastname: Ericsson
authors.forename: Folke
authors.initials: F
authors.lastname: Sjöberg
authors.forename: Maria
authors.initials: M
authors.lastname: Heijer
authors.forename: Hassan
authors.initials: H
authors.lastname: Dorani
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.forename: Maria
authors.initials: M
authors.lastname: Wollbratt
authors.forename: Ensio
authors.initials: E
authors.lastname: Norjavaara
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020536:Enzyme Activators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D005941:Glucokinase / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D019518:Postprandial Period; D016037:Single-Blind Method; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C576406:3-(2-hydroxy-1-methylethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(4-(methylsulfonyl)phenoxy)benzamide; D001549:Benzamides; D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D013450:Sulfones; D005941:Glucokinase