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Background and Objective: AZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects. Methods: Four cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected. Results: The pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (Tmax) of 1–2 h Creatine-normalized urine maximum concentration (Cmax) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60–600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E4 (LTE4) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed. Conclusions: The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5‐lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single‐blind, placebo‐controlled, first‐in‐human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4) production in whole blood and endogenous leukotriene E (LTE4) in urine. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half‐life of 10–12 h. Steady‐state levels were achieved after ∼3 days. After both SADs and MADs, a dose/concentration‐effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50) values in the lower nM range. Based on obtained result, AZD5718 is considered as a suitable drug candidate for future evaluation in patients with coronary artery disease (CAD). [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate the pharmacodynamics, pharmacokinetics and safety of the glucokinase activator AZD6370 after 1day 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 180mg) 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 180mg 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 180mg doses). Insulin secretion increased with dose, but absolute increases were relatively small in the fasted versus fed state (0–4h). Dosing AZD6370 twice or four-times over 1day 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. [Copyright &y& Elsevier]