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

Abstract

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 (AUC0–∝ 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.

Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction

“…The starting dose of 5 mg in cohort 1 was the same starting dose as previously evaluated in a SAD study and, although some accumulation was predicted following once‐daily dosing to steady‐state, exposures were predicted to be well below the highest doses/exposures explored in that study 10 . A period of 10 days was deemed sufficient to reach steady‐state conditions given the half‐life of AZD4831 as determined in the SAD study.…”

“…Samples for determination of AZD4831 in urine were analyzed by Covance Laboratories Ltd. AZD4831 and the stable labeled internal standard [ 13 C 3 15 N 2 ]AZD4831 were prepared from urine by sample dilution and analyzed by liquid chromatography tandem mass spectrometry. This method was validated prior to sample analysis in the range 20–20,000 nM in urine, using a 25 µL sample aliquot 10 …”

“…AZD4831 is a novel, potent, and selective MPOi with an in vitro half‐maximal inhibitory concentration of 0.7 nM for human MPO. The pharmacokinetics (PKs), safety, and tolerability, and the effect on uric acid, a down‐stream biomarker of MPO inhibition, following single ascending doses (SADs) in healthy volunteers has been reported 10 . The human plasma protein binding is 65%, and in vitro studies have indicated that CYP3A4/CYP3A5 is the predominant CYP isoform involved in the metabolism of AZD4831, although other elimination pathways are predicted to contribute to the overall elimination (i.e., non‐CYP450 mediated metabolism as well as renal clearance) 10 …”

A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019)

“…AZD4831 was shown to be well tolerated: no adverse effects have been observed except maculopapular rash but only at high doses (135 mg) and in 33% of the participants [77].…”

“…A high-fat and high-calorie meal led to a reduced absorption rate by 44% compared to the administration without food intake. It has been found also that AZD4831 has a long plasma half-life (t 1/2 = 38-50 h) and the main clearance route is renal [77]. In vitro metabolism studies have indicated that the cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 are involved in the metabolism of AZD4831 [77].…”