Open AccessInitial Clinical Experience with AZD5718, a Novel Once Daily Oral 5‐Lipoxygenase Activating Protein Inhibitor
Author(s) -
Ericsson Hans,
Nelander Karin,
LagerstromFermer Maria,
Balendran Clare,
Bhat Maria,
Chialda Ligia,
Gan LiMing,
Heijer Maria,
Kjaer Magnus,
Lambert John,
Lindstedt EvaLotte,
Forsberg GunBritt,
Whatling Carl,
Skrtic Stanko
Publication year - 2018
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12546
Subject(s) - lipoxygenase , arachidonate 5 lipoxygenase , medicine , pharmacology , chemistry , biochemistry , enzyme , arachidonic acid
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 (LTB 4 ) production in whole blood and endogenous leukotriene E (LTE 4 ) 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 LTB 4 and LTE 4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC 50 ) 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).