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

摘要

Aims: To assess the safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656in 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 receivedAZD1656 (7, 20, 40 or 80 mg) twice daily or placebo for 8 days in hospital. In part B, another 20 patients received, as outpatients, individuallytitrated AZD1656 15-45mg 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 wasrapidly absorbed and eliminated. An active metabolite was formed which had a longer half-life than AZD1656, but showed ~15% of thearea under the plasma concentration versus time curve from 0 to 24 h compared with that of AZD1656. Renal excretion of AZD1656 and themetabolite 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 to24% with AZD1656 versus placebo, depending on dose. No dose-related changes in serum insulin or C-peptide were observed with AZD1656at 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 plasmaglucose were observed.