Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits

Abstract

Apixaban has similar affinity for human and rabbit factor Xa (FXa). Rabbits are commonly used in development of thrombosis disease models; however, unlike in other species, apixaban demonstrated poor oral bioavailability (F = 3%) and a high clearance rate (2.55 l/h/kg) in rabbits. Oxidative metabolism of [14C] apixaban by liver microsomes was approximately 20 times faster in rabbits than in rats or humans. Following an intravenous (IV) dose of 5 mg/kg, circulating levels of [14C] apixaban decreased from the earliest sampling time (5 min) to undetectable at 4 h. After an oral dose of 30 mg/kg, levels of [14C] apixaban were only detected at 1 and 4 h. Radioactivity profiling showed that apixaban was a significant component in plasma only after IV administration; O-demethyl apixaban (M2), O-demethyl apixaban glucuronide (M14) and O-demethyl apixaban sulfate (M1) were prominent metabolites after both IV and oral administration. Studies of apixaban in rabbits showed a good correlation between apixaban concentrations and inhibition of FXa activity, prolongation of prothrombin time and modified prothrombin time, with no lag time between these ex vivo pharmacodynamic markers and plasma drug levels. The apixaban concentration required for 50% inhibition (IC50) of FXa activity ex vivo (0.22 +/- 0.02 microM) agreed with the IC50 from in vitro experiments in rabbit and human plasma. In summary, apixaban shows similar affinity for human and rabbit FXa. It produces a rapid onset of action, predictable concentration-dependent pharmacodynamic responses, and, unlike rats or humans, a rapid hepatic metabolism in rabbits.

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

“…Administration of apixaban was associated with a fast onset of action and concentration-dependent increases in plasma anti-Xa activity, consistent with the expected effects of a direct factor Xa inhibitor 12,24. As observed in previous studies, the time course of anti-Xa activity closely tracked the apixaban plasma concentration–time profile, with a direct linear relationship between the two that exhibited no temporal lag 12,25.…”

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

“…Addition of 3Ј-phosphoadenosine 5Ј-phosphosulfate, the sulfation cofactor, and human liver cytosol to the HLM incubations did not change the rate or profile of apixaban metabolism. Apixaban was also metabolized by HLM isolated from young donors, and the metabolite formation profiles were qualitatively similar to those for HLM from adults (Table 1) and comparison with previously identified metabolites in animals and humans (Zhang et al, , 2010, these three metabolites were identified as O-demethyl apixaban (M2) and two hydroxylated apixaban derivatives (M4 and M7).…”

“…Apixaban is efficacious and well tolerated in the treatment of patients with acute symptomatic deep vein thrombosis (Buller et al, 2008). After oral administration, apixaban was slowly metabolized and thus was mostly unchanged in the circulation although apixaban was metabolized by multiple pathways in animals and humans (Zhang et al, , 2010. The primary metabolic pathways of apixaban in humans included O-demethylation (M2) and hydroxylation (M4 and M7).…”

Correlation of Coagulation Markers and 4F-PCC-Mediated Reversal of Rivaroxaban in a Rabbit Model of Acute Bleeding

“…Furthermore, rabbit models have been found to be suitable models for assessment of FXa inhibitors. This is because they are comparable to humans in terms of in vitro anticoagulation effect of FXa inhibitors [43], and are more sensitive to small molecule FXa inhibitors than mice, rats or dogs [44,45]. In addition, the use of a randomised design and of both placebo and negative control groups allowed for a rigorous evaluation of rivaroxaban reversal with 4F-PCC.…”