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Drug Metabolism and Disposition Fast Forward
First published on October 2, 2008; DOI: 10.1124/dmd.108.023143

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Received for publication June 27, 2008.
Revised September 30, 2008.
Accepted for publication October 1, 2008.

APIXABAN METABOLISM AND PHARMACOKINETICS FOLLOWING ORAL ADMINISTRATION TO HUMANS

Nirmala Raghavan 1, Charles E Frost 1, Zhigang Yu 1, Kan He 1, Haiying Zhang 1, W Griffith Humphreys 1, Donald Pinto 1, Shiangyuan Chen 1, Samuel Bonacorsi 1, Pancras C Wong 1, Donglu Zhang 1*

1 Bristol-Myers Squibb

* Address correspondence to: E-mail: donglu.zhang{at}bms.com

Abstract

The metabolism and disposition of [14C]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 3-8 hours after dosing from Group 2 subjects. There were no serious adverse events (AEs) 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 (Cmax and AUC) in subjects with bile collection was generally similar to 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 FXa with elimination pathways that include metabolism and renal excretion.


Key words: biliary excretion, drug development, drug disposition, drug distribution, drug secretion, pharmacokinetics, sulfate conjugation


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D. Zhang, K. He, N. Raghavan, L. Wang, J. Mitroka, B. D. Maxwell, R. M. Knabb, C. Frost, A. Schuster, F. Hao, et al.
Comparative Metabolism of 14C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans
Drug Metab. Dispos., August 1, 2009; 37(8): 1738 - 1748.
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L. Wang, N. Raghavan, K. He, J. M. Luettgen, W. G. Humphreys, R. M. Knabb, D. J. Pinto, and D. Zhang
Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison
Drug Metab. Dispos., April 1, 2009; 37(4): 802 - 808.
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