Pharmacokinetics, Disposition, and Biotransformation of Laroprovstat in Humans: In Vivo and In Vitro Evaluations

Abstract Laroprovstat (AZD0780) is a small‐molecule, oral PCSK9 inhibitor being developed for hypercholesterolemia. In vitro experiments and a two‐part clinical study were conducted to characterize laroprovstat routes of elimination, metabolism, and absolute oral bioavailability. Laroprovstat was incubated in human hepatic spheroids from two different donors with and without ketoconazole to examine metabolite formation. A clinical study was conducted in eight healthy male participants, whereby in Part 1 each subject received a single oral dose of 60 mg as tablets of laroprovstat with a 100‐µg IV infusion of [ 14 C]laroprovstat solution to determine absolute oral bioavailability. In Part 2, a single oral dose of 60‐mg [ 14 C]laroprovstat solution was administered for disposition and biotransformation characterization. Based on in vitro studies, CYP3A are the predominant enzymes involved in the oxidative metabolism of laroprovstat, accounting for approximately 90% of laroprovstat metabolism. From the clinical study, laroprovstat is highly orally bioavailable, 78.4%. Laroprovstat was extensively metabolized with most of the dose excreted as oxidative metabolites with some additional conjugation. Only 15% and 6% of the dose was eliminated as parent in the urine and feces, respectively. No major circulating metabolites were identified that require further safety assessment or in vitro evaluation of DDI potential, aligned with the analysis of metabolites in plasma after repeated administration of laroprovstat from the MAD study. Renal elimination of total radioactivity was 64%, compared to 26% in the feces. Laroprovstat does not undergo significant chiral interconversion. Laroprovstat was well tolerated with no new safety concerns. These studies successfully characterized the ADME properties of laroprovstat.