Apixaban Anti-Xa

Clinical Information

Apixaban is an oral anticoagulant that prevents thrombin generation by inhibiting factor Xa produced as the result of both the intrinsic and extrinsic coagulation pathways.^1,2 This drug inhibits free and prothrombinase-associated factor Xa in a concentration-dependent manner.^3,4 Apixaban has a rapid onset reaching a maximal plasma concentration within one to three hours after oral administration.^5,6 Steady-state concentrations are reached within three days with a half-life of 9 to 14 hours in healthy adults.^5-7 Oral bioavailability of apixaban is not affected by food intake.^4,5 Apixaban is almost insoluble in water and exhibits high plasma protein binding (87%) in humans.⁶ Approximately one-fourth of apixaban is excreted by the kidneys about one-half by the fecal route.^5,6 Significant renal impairment results in decreased clearance and increases overall exposure to the drug.⁶

The P-glycoprotein (P-gp) multidrug transporter protein facilitates the transport of apixaban across cell membranes and influences the absorption and disposition of the drug in vivo.^8,9 Apixaban is metabolized by the mixed function oxidase, cytochrome P450 3A4/5 (CYP3A4/5).⁵ Drugs that affect the activity of CYP3A4/5 and P-glycoprotein can potentially affect the pharmacokinetic profile of apixaban, Apixaban is transported across the intestinal wall by P-glycoprotein, and drugs that induce or inhibit P-glycoprotein activity may decrease or increase the levels of apixaban, respectively.

Routine therapeutic monitoring of apixaban level is not required because of the drug's relatively wide therapeutic index. Despite the use of fixed doses of apixaban, determination of the amount of drug present in a given individual may be valuable in several clinical situations, such as patients who experience bleeding or treatment failure.^10,11 Determination of drug concentration may also be needed in patients who require thrombolytic therapy, surgery, or in those who have suffered trauma. It may also be of value in patients with renal insufficiency, advanced age, and low body weight.^10,11 Measurement of levels can inform clinicians with concerns regarding patient compliance and adherence to therapy as well as in situations of suspected or known overdose.

Apixaban can be measured using a validated liquid chromatography/mass spectrometry (HPLC/MS-MS) method as well as a validated chromogenic anti-Xa method. Use of liquid LC/MS-MS provides highly accurate measurement of apixaban concentrations without the variable interferences associated with traditional clot-based and chromogenic assays.¹² In fact, studies performed using the LabCorp LC/MS-MS method indicate that the assayed drug recovery was unaffected by the presence of lupus anticoagulants or heparin administration. Factor VIII deficiency and multiple factor deficiency associated with coumadin treatment had no effect on the recovery of drug. A chromogenic anti-Xa assay calibrated with an apixaban standard can accurately determine apixaban concentration in plasma, although this assay is not specific for apixaban and will detect any anti-Xa anticoagulant, both direct and indirect.¹¹

Therapeutic Range

In the Aristotle trial in nonvalvular atrial fibrillation patients receiving a 5 mg bid dose yielded a median C_max apixaban value of 171 ng/mL with a 91-321 ng/mL range for the 5th to 95th percentile. A 2.5 mg bid dose yielded a median C_max value of 123 ng/mL with a 68.5−221 ng/mL range for the 5th to 95th percentile.¹³

In the AMPLIFY trial in venous thromboembolism treatment, patients receiving a 5 mg bid dose yielded a median C_max value of 132 ng/mL with a 58.6−302.2 ng/mL range for the 5th to 95th percentile. A 2.5 mg bid dose yielded a median C_max value of 67 ng/mL with a 29.7−153.2 ng/mL range for the 5th to 95th percentile.¹²