Dataset Information

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).

SUBMITTER: Ericsson H

PROVIDER: S-EPMC5944575 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Ericsson Hans H Nelander Karin K Lagerstrom-Fermer Maria M Balendran Clare C Bhat Maria M Chialda Ligia L Gan Li-Ming LM Heijer Maria M Kjaer Magnus M Lambert John J Lindstedt Eva-Lotte EL Forsberg Gun-Britt GB Whatling Carl C Skrtic Stanko S

Clinical and translational science 20180308 3

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<sub>4</sub> ) production in whole blood and endogenous leukotriene E (LTE<sub>4</sub> ) ...[more]

PMID: 29517132

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Project description:Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1-4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be <50%, and Thrombolysis In Myocardial Infarction flow grade must be ? 2. Enrolled participants receive standard care plus oral AZD5718 200 mg, 50 mg, or placebo once daily for up to 12 weeks (extended from 4 weeks by protocol amendment). The planned sample size is 100 participants randomized to 12 weeks' treatment. Change in urine leukotriene E4 levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease.

Project description:To quantify contrast material enhancement of breast lesions scanned with dedicated breast computed tomography (CT) and to compare their conspicuity with that at unenhanced breast CT and mammography.Approval of the institutional review board and the Radiation Use Committee and written informed consent were obtained for this HIPAA-compliant study. Between September 2006 and April 2009, 46 women (mean age, 53.2 years; age range, 35-72 years) with Breast Imaging Reporting and Data System category 4 or 5 lesions underwent unenhanced breast CT and contrast material-enhanced breast CT before biopsy. Two radiologists independently scored lesion conspicuity for contrast-enhanced breast CT versus mammography and for contrast-enhanced breast CT versus unenhanced breast CT. Mean lesion voxel intensity was measured in Hounsfield units and normalized to adipose tissue intensity on manually segmented images obtained before and after administration of contrast material. Regression models focused on conspicuity and quantified enhancement were used to estimate the effect of pathologic diagnosis (benign vs malignant), lesion type (mass vs calcifications), breast density, and interradiologist variability.Fifty-four lesions (25 benign, 29 malignant) in 46 subjects were analyzed. Malignant lesions were seen significantly better at contrast-enhanced breast CT than at unenhanced breast CT (P < .001) or mammography (P < .001). Malignant calcifications (malignant lesions manifested mammographically as microcalcifications only, n = 7) were seen better at contrast-enhanced breast CT than at unenhanced breast CT (P < .001) and were seen similarly at contrast-enhanced breast CT and mammography. Malignant lesions enhanced 55.9 HU +/- 4.0 (standard error), whereas benign lesions enhanced 17.6 HU +/- 6.1 (P < .001). Ductal carcinoma in situ (n = 5) enhanced a mean of 59.6 HU +/- 2.8. Receiver operating characteristic curve analysis of lesion enhancement yielded an area under the receiver operating characteristic curve of 0.876.Conspicuity of malignant breast lesions, including ductal carcinoma in situ, is significantly improved at contrast-enhanced breast CT. Quantifying lesion enhancement may aid in the detection and diagnosis of breast cancer.

Dataset Information

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

Publications

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

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