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

Hans Ericsson, Karin Nelander, Maria Lagerstrom-Fermer, Clare Balendran, Maria Bhat, Ligia Chialda, Li-Ming Gan, Maria Heijer, Magnus Kjaer, John Lambert, Eva-Lotte Lindstedt, Gun-Britt Forsberg, Carl Whatling, Stanko Skrtic, Hans Ericsson, Karin Nelander, Maria Lagerstrom-Fermer, Clare Balendran, Maria Bhat, Ligia Chialda, Li-Ming Gan, Maria Heijer, Magnus Kjaer, John Lambert, Eva-Lotte Lindstedt, Gun-Britt Forsberg, Carl Whatling, Stanko Skrtic

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).

© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Geometric mean ±SD for plasma concentration‐time profiles by treatment following single ascending doses of AZD5718, n = 6 per dose. Insert: first 4 h after dose.
Figure 2
Figure 2
Geometric mean ± SD for plasma concentration‐time profiles by treatment following multiple ascending doses of AZD5718 (after first and last dose), n = 6 per dose. Insert; first 4 h after dose.
Figure 3
Figure 3
Geometric mean ± SD Ctrough concentration‐time profiles by treatment following multiple ascending doses of AZD5718, n = 6 per dose.
Figure 4
Figure 4
Evaluation of dose proportionality: area under the concentration‐time curve (AUC), peak plasma concentration (Cmax), and Ctrough in single ascending dose (SAD) and AUC0–24h, Cmax, and Ctrough after last dose in multiple ascending dose (MAD) vs. dose of AZD5718, n = 6 per cohort. Dashed line linear regression.
Figure 5
Figure 5
Geometric mean concentration‐time profiles (light green) and geometric mean leukotriene E4 (LTE4) (dashed blue) and leukotriene B4 (LTB4) (solid purple) inhibition‐time profiles, following single ascending doses (SADs) and multiple ascending doses (MADs) of AZD5718, n = 6 per dose.
Figure 6
Figure 6
Leukotriene E4 (LTE4) (blue triangles) and leukotriene B4 (LTB4) (purple circles) inhibition vs. concentration at trough for single ascending doses and multiple ascending doses. Included lines are based on maximum effect (Emax) model estimates.

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