Pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - in rats and dogs

• Published in: Xenobiotica Vol. 35; no. 9; pp. 891 - 910
• Main Authors: Weinz, C., Buetehorn, U., Daehler, H.-P., Kohlsdorfer, C., Pleiss, U., Sandmann, S., Schlemmer, K.-H., Schwarz, T., Steinke, W.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.09.2005; Taylor & Francis
• Subjects: absorption; Administration, Oral; Animals; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; distribution; Dogs; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; excretion; Factor Xa inhibitor; Factor Xa Inhibitors; Female; Male; Morpholines - administration & dosage; Morpholines - pharmacokinetics; pharmacokinetics; Preclinical; protein binding; Rats; Rats, Wistar; Rivaroxaban; Thiophenes - administration & dosage; Thiophenes - pharmacokinetics; whole-body autoradiography
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498250500250493

The pharmacokinetics of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor - were investigated in rats and dogs in support of preclinical safety studies and clinical development. BAY 59-7939 was rapidly absorbed after oral dosing, with an absolute bioavailability of 57-66% in rats, and 60-86% in dogs. Plasma pharmacokinetics of BAY 59-7939 were linear across the investigated dose range (1-10 mg kg−1 in rats, 0.3-3 mg kg−1 in dogs). Plasma clearance was low: 0.4 l kg−1 h−1 in rats and 0.3 l kg−1 h−1 in dogs; volume of distribution (Vss) was moderate: 0.3 l kg−1 in rats, and 0.4 l kg−1 in dogs. The elimination half-life after oral administration was short in both species (0.9-2.3 h). Whole-body autoradiography showed moderate tissue affinity. No retention or small volume enrichments of BAY 59-7939-related radioactivity were observed. The plasma-protein binding of BAY 59-7939 was high, species dependent and fully reversible. BAY 59-7939 was rapidly excreted in rats and dogs, and was not irreversibly retained. A dual mode of excretion (biliary faecal and renal) was observed. In summary, BAY 59-7939 had a favourable, predictable pharmacokinetic profile, with high oral bioavailability and a dual route of excretion.