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Phase 1 Pharmacokin...
Phase 1 Pharmacokinetic Study of AZD5718 in Healthy Volunteers: Effects of Coadministration With Rosuvastatin, Formulation and Food on Oral Bioavailability
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Ericsson, H. (author)
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Nelander, K. (author)
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Heijer, M. (author)
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Kjaer, M. (author)
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Lindstedt, E. L. (author)
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Albayaty, M. (author)
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Forte, P. (author)
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Lagerstrom-Fermer, M. (author)
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- Skrtic, Stanko, 1970 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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(creator_code:org_t)
- Wiley, 2020
- 2020
- English.
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In: Clinical Pharmacology in Drug Development. - : Wiley. - 2160-7648 .- 2160-763X. ; 9:3, s. 411-421
- Related links:
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https://accp1.online...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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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 B-4 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- 5-lipoxygenase-activating protein
- coronary artery disease
- drug-drug
- interaction
- leukotriene
- phase 1 clinical trial
- statin
- 5-lipoxygenase
- expression
- pathway
- risk
- Pharmacology & Pharmacy
Publication and Content Type
- ref (subject category)
- art (subject category)
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