Initial Clinical Experience with AZD5718, a Novel Once Daily Oral 5‐Lipoxygenase Activating Protein Inhibitor

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).

Phase 1 Pharmacokinetic Study of AZD5718 in Healthy Volunteers: Effects of Coadministration With Rosuvastatin, Formulation and Food on Oral Bioavailability

“…Instead, post hoc pharmacodynamic simulations were performed using the observed pharmacokinetic profiles of AZD5718 to predict the effect of multiple doses of AZD5718 on plasma leukotriene B 4 levels. These simulations relied on a pharmacokinetic‐pharmacodynamic model, which was developed based on results from the first‐in‐human phase 1 study . This approach allowed the results of the present study to support the design of the currently ongoing phase 2a study of AZD5718 (NCT03317002).…”

“…Samples for determination of AZD5718 in plasma were analyzed by Covance Laboratories (Harrogate, UK), and samples for determination of rosuvastatin in plasma were analyzed by Covance (Madison, Wisconsin) . The bioanalytical methods were validated prior to sample analysis, and all study samples were analyzed within the known stability period.…”

“…Pharmacodynamic simulations were performed using the observed pharmacokinetic profiles of AZD5718 to predict plasma leukotriene B 4 levels after multiple doses. These simulations relied on a population pharmacokinetic‐pharmacodynamic model developed based on data from the first‐in‐human phase 1 study of AZD5718 …”

“…AZD5718 (Figure ) is a novel and potent FLAP inhibitor that blocks leukotriene B 4 production in human leukocytes, with a half‐maximal inhibitory concentration (IC 50 ) of 39 nM in vitro . A first‐in‐human phase 1 study of AZD5718 in healthy volunteers showed that single oral doses of 25‐1200 mg and multiple doses of 60‐600 mg were well tolerated, with no identified safety concerns (NCT02632526) . Following administration of an oral suspension, AZD5718 was rapidly absorbed and had a terminal half‐life of 10‐12 hours in plasma, with steady‐state levels reached after about 3 days .…”

“…In vitro studies indicate that cytochrome P450 (CYP) 3A4 and CYP3A5 are involved in the metabolism of AZD5718, with glucuronidation by uridine 5’‐diphosphate glucuronosyltransferases 1A1, 1A3, and 1A4 also contributing to metabolism . AZD5718 does not inhibit CYP isoforms 1A2, 2C8, 2C9, 2C19, 2D6, or 3A4 (IC 50 > 20 µM) or P‐glycoprotein (IC 50 > 100 µmol/L).…”