Pharmacokinetics, Pharmacodynamics, and Tolerability of AZD5718, an Oral 5-Lipoxygenase-Activating Protein (FLAP) Inhibitor, in Healthy Japanese Male Subjects

• Published in: Clinical drug investigation 2021-10, Vol.41 (10), p.895-905
• Main Authors: Knöchel, Jane, Nelander, Karin, Heijer, Maria, Lindstedt, Eva-Lotte, Forsberg, Gun-Britt, Whatling, Carl, Shimada, Hitoshi, Han, David S., Gabrielsen, Anders, Garkaviy, Pavlo, Ericsson, Hans
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase-Activating Proteins; Area Under Curve; Cardiovascular disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Healthy Volunteers; Hospitalization; Humans; Internal Medicine; Japan; Kidney diseases; Male; Medical laboratories; Medicine; Medicine & Public Health; Original; Original Research Article; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Proteins; Pyrazoles; Vital signs
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-021-01078-7

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 ( T max ) of 1–2 h Creatine-normalized urine maximum concentration ( C max ) 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 E 4 (LTE 4 ) 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.