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

Ericsson, Henrik; Nelander, Karin; Lagerström-Fermér, Maria; Balendran, Clare A.; Bhat, Maria; Chialda, Ligia; Gan, Li‐Ming; Heijer, Maria; Kjaer, Magnus; Lambert, John M.; Lindstedt, Eva-Lotte; Forsberg, Gun-Britt; Whatling, Carl; Skrtic, Stanko

doi:10.1111/cts.12546

Cited by 20 publications

(49 citation statements)

References 17 publications

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“…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).…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

“…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 …”

Section: Methodsmentioning

confidence: 99%

“…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 .…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Ericsson

Nelander

Heijer

et al. 2019

Clinical Pharm in Drug Dev

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AZD5718 is a first‐in‐class small‐molecule anti‐inflammatory drug with the potential to reduce the residual risk of cardiovascular events after myocardial infarction in patients receiving lipid‐lowering statin therapy. Leukotrienes are potent proinflammatory and vasoactive mediators synthesized in leukocytes via 5‐lipoxygenase and 5‐lipoxygenase‐activating protein (FLAP). AZD5718 is a FLAP inhibitor that dose‐dependently reduced leukotriene biosynthesis in a first‐in‐human study. We enrolled 12 healthy men in a randomized, open‐label, crossover, single‐dose phase 1 pharmacokinetic study of AZD5718 to investigate a potential drug‐drug interaction with rosuvastatin, and the effects of formulation and food intake (ClinicalTrials.gov identifier: NCT02963116). Rosuvastatin (10 mg) were absorbed more rapidly when coadministered with AZD5718 (200 mg), probably owing to weak inhibition of hepatic statin uptake, but relative bioavailability was unaffected (geometric least‐squares mean ratio [GMR], 100%; 90% confidence interval [CI], 86%‐116%). AZD5718 pharmacokinetics were unaffected by coadministration of rosuvastatin. AZD5718 (200 mg) was absorbed less rapidly when formulated as tablets than oral suspension, with reduced relative bioavailability (GMR, 72%; 90%CI, 64%‐80%). AZD5718 absorption was slower when 200‐mg tablets were taken after a high‐fat breakfast than after fasting, but relative bioavailability was unaffected (GMR, 96%; 90%CI, 87%‐106%). In post hoc pharmacodynamic simulations, plasma leukotriene B4 levels were inhibited by >90% throughout the day following once‐daily AZD5718, regardless of formulation or administration with food. AZD5718 was well tolerated, with no severe or serious adverse events. These data supported the design of a phase 2a efficacy study of AZD5718 in patients with coronary artery disease.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Ericsson

Nelander

Heijer

et al. 2019

Clinical Pharm in Drug Dev

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Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

Li,

Lindmark,

Amilon

et al. 2024

Pharmacology Res & Perspec

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In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half‐life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug‐related exposure (DRE), while a direct N‐glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.

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

et al. 2021

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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.

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

Cited by 20 publications

References 17 publications

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

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

Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

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

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