Metabolism and Excretion of Rivaroxaban, an Oral, Direct Factor Xa Inhibitor, in Rats, Dogs, and Humans

Abstract

ABSTRACT:Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [ 14 C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/ intravenously) and dogs (orally), respectively. A single oral dose of [ 14 C]rivaroxaban (10 mg) was administered to healthy human males (n ‫؍‬ 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and >92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.Rivaroxaban is a novel, oral, direct factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. More recently, it has received approval in Canada and the European Union for use in the prevention of venous thromboembolism in patients undergoing elective total hip or knee replacement surgery. Rivaroxaban is a selective inhibitor not only of free FXa (K i 0.4 nM), but also of prothrombinase activity and fibrinassociated FXa activity Perzborn et al., 2005). In vitro, rivaroxaban was shown to inhibit thrombin generation and prolong clotting times Perzborn et al., 2005) and, in vivo, it had potent antithrombotic effects in a variety of animal venous and arterial thrombosis models Biemond et al., 2007).Pharmacokinetic (PK) studies of rivaroxaban in rats and dogs have been reported previously (Weinz et al., 2005). These studies demonstrated that rivaroxaban was absorbed rapidly after oral dosing (absolute bioavailability 57-66 and 60 -86% in rats and dogs, respectively), had a favorable PK profile with dose proportional increases in area under the concentration-time curve (AUC) and was rapidly excreted via renal and fecal/biliary routes. Rivaroxaban has also been shown to demonstrate dose-proportional pharmacokinetics and predictable pharmacodynamics in single (up to 80 mg)-and multipledose studies in healthy subjects and patients with no evidence of accumulation (Kubitza et ...

Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

“…For Equation (7), f m,CYP3A + f m,CYP2J2 + f m,non-CYP = 1; [I] is operating inhibitor concentration (see below), and K i is the reversible inhibition constant, K deg,CYP3A is the apparent first order degradation rate constant of CYP3A, and K obs is the apparent inactivation rate constant in the presence of erythromycin according to Equation (8).…”

“…Liver metabolism and kidney excretion account for approximately 60% and 40% of the elimination of rivaroxaban, respectively [1, [5][6][7][8]. In the liver, cytochrome P450 enzymes (CYPs) CYP3A, CYP2J2, and hydrolytic enzymes each contribute approximately one-third of the hepatic metabolism of rivaroxaban [1, [5][6][7][8].…”

In Vitro Metabolism of Rivaroxaban, an Oral, Direct Factor Xa Inhibitor, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans

“…Pharmacokinetic studies in rats and dogs (Weinz et al, 2005) and in humans (Weinz et al, 2009) have demonstrated that rivaroxaban was absorbed rapidly after oral dosing, had a favorable and predictable pharmacokinetic profile, and was excreted rapidly via renal and faecal/biliary routes.…”

Adherence to the Use of New Oral Anticoagulants in Patients With Atrial Fibrillation – the Way to Solve the Problem of Efficacy and Safety of Treatment

“…Ривароксабан имеет двойной путь выведения: одна треть примененной дозы удаляется из организма через поч-ки в неизменном виде, а остальные две трети метабо-лизируются в печени. Приблизительно половина ме-таболитов затем выделяется с фекалиями, другая по-ловина -через почки [25]. Коррекции дозы препара-та в зависимости от возраста, пола или веса пациента не требуется.…”