Preclinical Pharmacokinetic and Metabolism of Apixaban, a Potent and Selective Factor Xa Inhibitor.

Abstract

Apixaban is a potent, orally available, highly selective, and reversible factor Xa inhibitor, and currently under development for prevention and treatment of thrombosis. The preclinical pharmacokinetic and metabolism attributes of apixaban feature a small volume of distribution, a low systemic clearance, good oral bioavailability, multiple elimination pathways and minimal potential for drug-drug interactions. Apixaban is well absorbed in chimpanzees, dogs and rats with a mean oral bioavailability of 51, 88 and 34%, respectively. The mean volume of distribution of apixaban is 0.17, 0.29 and 0.31 L/kg in chimpanzees, dogs and rats, respectively, suggesting apixaban is primarily distributed (30–50%) to blood where the therapeutic action resides. The small volume is not due to extensive plasma protein binding, but possibly attributed to limited extravascular tissue distribution, given that the unbound fraction is approximately 13, 5, 8 and 4% in human, chimpanzee, dog and rat serum, respectively. The systemic clearance is <3% of hepatic blood flow in chimpanzees (0.018 L/h/kg) and dogs (0.052 L/h/kg), and <10% in rats (0.26 L/h/kg). Consistent with this low clearance, the in vitro metabolic clearance of apixaban is low, as indicated by the lack of significant metabolism in human liver microsomes and hepatocytes, and in chimpanzee and dog liver microsomes. The primary metabolite identified in vitro is the O-demethylated product which is formed mainly by CYP3A4 in human liver microsomes. The elimination of apixaban involves multiple pathways including renal and intestinal excretion of the parent and metabolism. The biliary clearance is low in dogs, accounting for approximately 2% of the systemic clearance. Apixaban did not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 activities in cDNA-expressed enzyme systems and human liver microsomes, nor induced 1A2, 2B6 and CYP3A4 in human hepatocytes. No glutathione adduct with apixaban was formed in dog and rat, and in human hepatocytes and liver microsomal incubation in the presence of glutathione, suggesting low potential for the formation of reactive metabolites. In conclusion, apixaban shows excellent pharmacokinetic and metabolic properties for clinical development.