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

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 (V_ss) 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.

Kewords: :

• Preclinical
• pharmacokinetics
• Factor Xa inhibitor
• absorption
• distribution
• excretion
• protein binding
• whole-body autoradiography