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

Artikel i vetenskaplig tidskrift
Författare H. Ericsson
K. Nelander
M. Heijer
M. Kjaer
E. L. Lindstedt
M. Albayaty
P. Forte
M. Lagerstrom-Fermer
Stanko Skrtic
Publicerad i Clinical Pharmacology in Drug Development
Sidor 11
ISSN 2160-7648
Publiceringsår 2019
Publicerad vid Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
Sidor 11
Språk en
Länkar dx.doi.org/10.1002/cpdd.756
Ämnesord 5-lipoxygenase-activating protein, coronary artery disease, drug-drug, interaction, leukotriene, phase 1 clinical trial, statin, 5-lipoxygenase, expression, pathway, risk, Pharmacology & Pharmacy
Ämneskategorier Farmakologi

Sammanfattning

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.

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