title: Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  To assess the safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  This randomized, single-blind, placebo-controlled, monotherapy study was carried out in two parts. In part A, 32 patients received AZD1656 (7, 20, 40 or 80 mg) twice daily or placebo for 8 days in hospital. In part B, another 20 patients received, as outpatients, individually titrated AZD1656 15-45 mg twice daily or placebo for 28 days. Safety, pharmacokinetics and pharmacodynamic variables were evaluated.
  
  
  RESULTS
  AZD1656 was generally well tolerated. Pharmacokinetics of AZD1656 were virtually dose- and time-independent. AZD1656 was rapidly absorbed and eliminated. An active metabolite was formed which had a longer half-life than AZD1656, but showed ∼15% of the area under the plasma concentration versus time curve from 0 to 24 h compared with that of AZD1656. Renal excretion of AZD1656 and the metabolite was low. In part A, fasting plasma glucose (FPG) was reduced by up to 21% and mean 24-h plasma glucose was reduced by up to 24% with AZD1656 versus placebo, depending on dose. No dose-related changes in serum insulin or C-peptide were observed with AZD1656 at the end of treatment. Results in part B confirmed the glucose-lowering effect of AZD1656 versus placebo.
  
  
  CONCLUSIONS
  AZD1656 was well tolerated with predictable pharmacokinetics in patients with T2DM. Dose-dependent reductions in plasma glucose were observed.
authors: Profil Institute for Clinical Research, Chula Vista, CA, USA.
authors: L A
authors: LA
authors: Morrow
authors: M
authors: M
authors: Leonsson-Zachrisson
authors: H
authors: H
authors: Ericsson
authors: M
authors: M
authors: Wollbratt
authors: M
authors: M
authors: Knutsson
authors: M
authors: M
authors: Hompesch
authors: E
authors: E
authors: Norjavaara
mesh_terms: D000328:Adult; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects; D005941:Glucokinase / Q000187:drug effects* / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000187:drug effects; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016037:Single-Blind Method; D016896:Treatment Outcome
chemical_list: D001384:Azetidines; D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D010446:Peptide Fragments; D011719:Pyrazines; C576407:AZD1656; C517652:hemoglobin A1c protein, human; C049962:gastric inhibitory polypeptide (1-39)