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

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Abstract
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.