Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits.
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.
Zhang
Donglu
D
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
He
Kan
K
Raghavan
Nirmala
N
Wang
Lifei
L
Crain
Earl J
EJ
He
Bing
B
Xin
Baomin
B
Luettgen
Joseph M
JM
Wong
Pancras C
PC
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D065427:Factor Xa Inhibitors; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011728:Pyridones / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits
D000925:Anticoagulants; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban