Apixaban metabolism and pharmacokinetics after oral administration to humans.
The metabolism and disposition of [(14)C]apixaban, an orally bioavailable, highly selective, and direct acting/reversible factor Xa inhibitor, was investigated in 10 healthy male subjects without (group 1, n=6) and with bile collection (group 2, n=4) after a single 20-mg oral dose. Urine, blood, and feces samples were collected from all subjects. Bile samples were also collected for 3 to 8 h after dosing from group 2 subjects. There were no serious adverse events or discontinuations due to adverse effects. In plasma, apixaban was the major circulating component and O-demethyl apixaban sulfate, a stable and water-soluble metabolite, was the significant metabolite. The exposure of apixaban (C(max) and area under the plasma concentration versus time curve) in subjects with bile collection was generally similar to that in subjects without bile collection. The administered dose was recovered in feces (group 1, 56.0%; group 2, 46.7%) and urine (group 1, 24.5%; group 2, 28.8%), with the parent drug representing approximately half of the recovered dose. Biliary excretion represented a minor elimination pathway (2.44% of the administered dose) from group 2 subjects within the limited collection period. Metabolic pathways identified for apixaban included O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban. Thus, apixaban is an orally bioavailable inhibitor of factor Xa with elimination pathways that include metabolism and renal excretion.
Raghavan
Nirmala
N
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543-4000, USA.
Frost
Charles E
CE
Yu
Zhigang
Z
He
Kan
K
Zhang
Haiying
H
Humphreys
W Griffith
WG
Pinto
Donald
D
Chen
Shiangyuan
S
Bonacorsi
Samuel
S
Wong
Pancras C
PC
Zhang
Donglu
D
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet
D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban