Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus

• Published in: Diabetes, obesity & metabolism Vol. 14; no. 12; pp. 1114 - 1122
• Main Authors: Morrow, L. A., Leonsson-Zachrisson, M., Ericsson, H., Wollbratt, M., Knutsson, M., Hompesch, M., Norjavaara, E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2012; Wiley Subscription Services, Inc
• Subjects: Adult; Azetidines - administration & dosage; Azetidines - adverse effects; Azetidines - pharmacokinetics; Azetidines - pharmacology; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Dose-Response Relationship, Drug; Female; Gastric Inhibitory Polypeptide - drug effects; Glucagon-Like Peptide 1 - drug effects; glucokinase; Glucokinase - drug effects; Glucokinase - metabolism; glucokinase activator; Glucose; Glycated Hemoglobin A - drug effects; Glycated Hemoglobin A - metabolism; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Incretins - metabolism; Insulin - metabolism; Male; Middle Aged; Peptide Fragments - drug effects; Plasma; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Single-Blind Method; Treatment Outcome; type 2 diabetes mellitus; type 2 diabetes mellitus; glucokinase activator; glucokinase
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2012.01661.x

Aims
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.