Safety, tolerability, pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized, placebo‐controlled, phase I study in healthy volunteers

摘要

Aims Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation‐related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831. Methods In this randomized, single‐blind, placebo‐controlled, phase I, first‐in‐human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405?mg) or placebo, after overnight fasting. After at least 7?days' washout, one cohort additionally received AZD4831 45?mg after a high‐calorie meal. Results Forty men participated in the study (eight per cohort: AZD4831, n ?=?6; placebo, n ?=?2). AZD4831 distributed rapidly into plasma, with a half‐life of 38.2–50.0?hours. The area under the plasma concentration–time curve (AUC) increased proportionally with dose (AUC 0–∝ slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half‐life ( n ?=?4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) μmol L ?1 with AZD4831 135?mg and 405?mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified. Conclusions AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half‐life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831.