Apixaban: A Novel Oral Inhibitor of Factor Xa

Edith Nutescu, Pharm.D., FCCP

Disclosures

Am J Health Syst Pharm. 2012;69(13):1113-1126. 

In This Article

Pharmacokinetics

The pharmacokinetic properties of apixaban have been described in detail. In healthy male volunteers, apixaban was rapidly absorbed after oral administration, with a time to maximum plasma apixaban concentration of about 1 hour.[30] The elimination half-life for apixaban in healthy subjects is approximately 12 hours.[30] Results from a multiple ascending-dose study demonstrated that apixaban 2.5–25 mg twice daily reached steady-state plasma concentrations in three days, with mild accumulation (accumulation index, 1.3–1.9), dose-proportional drug exposure, and a time to maximum plasma concentration of 3.5 hours.[31] Increases in clotting time test results were observed after the first dose of apixaban.

Most of the administered dose of apixaban (>50%) is recovered in feces, and about 25% is recovered in urine, with the parent drug representing approximately half of the recovered dose.[30] Metabolic pathways identified for apixaban included O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban.[30,32] Experiments with human complementary DNA-expressed cytochrome P-450 (CYP) isoenzymes and CYP chemical inhibitors and their correlation with CYP activities in individual human liver microsomes revealed that the oxidative metabolism of apixaban for the formation of all metabolites was predominantly catalyzed by CYP3A4/5, with minor contributions made by CYP1A2 and CYP2J2.[33] The contributions of CYP2C8, CYP2C9, and CYP2C19 to the metabolism of apixaban were less important. These results raise the possibility that the pharmacokinetics of apixaban may be altered by other drugs that are substrates for or inducers or inhibitors of CYP3A4/5 (e.g., statins, antiretrovirals, antihypertensives, antibiotics). However, the fact that over 50% of the administered dose of apixaban is excreted as unchanged parent drug reduces the overall metabolic potential for a drug–drug interaction with apixaban.[32,33] Apixaban exposure is not affected by the consumption of food before or after drug administration.[34]

Results from additional studies have shown that the pharmacokinetics of apixaban is not substantially altered in special patient populations or as a function of race or ethnicity. The single- and multiple-dose pharmacokinetics and pharmacodynamics of apixaban in Japanese and Chinese subjects appear similar to those in white subjects.[35,36,37] In addition, the pharmacokinetics of apixaban is not substantially changed in patients with mild or moderate hepatic impairment.[38] The area under the plasma concentration–time curve (AUC) for apixaban was 32% higher in elderly subjects compared with younger volunteers; only a modest increase was seen in women versus men.[39] Additional studies have indicated no effect of impaired renal function on the peak concentration of apixaban. However, in individuals with mild, moderate, and severe renal impairment (creatinine clearance of 51–80, 30–50, and 15–29 mL/min, respectively), plasma apixaban concentrations (as indicated by AUC) were increased by 16%, 29%, and 44%, respectively, compared with values for individuals with normal creatinine clearance.[40] Renal impairment had no evident effect on the relationship between plasma apixaban concentration and anti-factor Xa activity.[40]

Not surprisingly, coadministration of apixaban with other anticoagulants or with antiplatelet agents has the potential to increase the risk of bleeding. An additive effect of apixaban and enoxaparin on anti-factor Xa activity was observed when they were administered together in healthy volunteers.[41] Results from the APPRAISE-1 trial in patients diagnosed with a recent ACS event indicated that the use of apixaban by patients who were also receiving clopidogrel or clopidogrel plus aspirin resulted in a dose-related increase in the rate of major or clinically relevant nonmajor bleeding, which was more pronounced in patients taking aspirin plus clopidogrel than in those taking aspirin alone.[42]

The oxidative metabolism of apixaban by CYP3A4/5 and the fact that apixaban is a substrate for P-glycoprotein (Pgp) create the potential for drug interactions.[30] Coadministration of apixaban with ketoconazole (400 mg orally once a day), a strong inhibitor of both CYP3A4 and Pgp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban maximum concentration.[43] The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and Pgp (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir).[40,43] Diltiazem hydrochloride (360 mg orally once a day), a moderate CYP3A4 and a weak Pgp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in maximum plasma apixaban concentration.[43] Naproxen (500 mg orally, single dose), an inhibitor of Pgp but not an inhibitor of CYP3A4, led to a 1.5-fold and a 1.6-fold increase in mean apixaban AUC and maximum concentration, respectively.[40] No dosage adjustment is required for apixaban when coadministered with less-potent inhibitors of CYP3A4 or Pgp.[40] Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and Pgp, led to a decrease of 54% in mean apixaban AUC and a decrease of 42% in maximum plasma apixaban concentration.[44] The concomitant use of apixaban with other strong CYP3A4 and Pgp inducers (e.g., phenytoin, carbamazepine, phenobarbital, St. John's wort) may also lead to reduced plasma apixaban concentrations.[40] No dosage adjustment is required for apixaban during concomitant therapy with such agents; however, strong inducers of both CYP3A4 and Pgp should be coadministered with caution.[40] No clinically significant pharmacokinetic interactions were observed when apixaban was coadministered with atenolol, famotidine, digoxin, or naproxen.[40,45,46]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....