Rivaroxaban

Plasma

1 mL

0.5 mL (Note: This volume does not allow for repeat testing.)

Blue-top (citrate) tube (preferred), lavender-top (EDTA) tube, or green-top (heparin) tube

Measurement of drug level in order to monitor therapeutic level and/or diagnose under-dosage or potential toxicity

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

Liquid chromatography/tandem mass spectrometry (LC/MS-MS)

Rivaroxaban (Xarelto®) is an oral anticoagulant that prevents thrombin generation by inhibiting factor Xa produced as the result of both the intrinsic and extrinsic coagulation pathways.^1-4 This low molecular weight drug (436 g/mol) inhibits free, prothrombinase-bound and clot-associated factor Xa in a concentration-dependent manner.³ In vitro studies have demonstrated that rivaroxaban prolongs the initiation phase of thrombin generation and reduces the thrombin burst produced in the propagation phase.³ The product labeling from December 2011 approves the use of rivaroxaban for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery (PI)

Rivaroxaban has a predictable clinical pharmacologic profile, providing the basis for the use of a fixed-dose regimen with no need for dose adjustment irrespective of age, weight, and gender. The drug has a rapid onset reaching a maximal plasma concentration within two to four hours after oral administration.^1,2,5,6 The in vivo half-life has been determined to be 7 to 11 hours in young people and 11 to 13 hours for elderly subjects.^6,7 The oral bioavailability of rivaroxaban is high (80% to 100%) and is not affected by food intake.^6,8 At single daily doses up to 15 mg administered orally to healthy subjects, rivaroxaban displays near linear pharmacokinetics with no significant accumulation after repeat dosing.^1,2,5 Rivaroxaban is almost insoluble in water and exhibits high plasma protein binding (92% to 95%) in humans, with serum albumin being the main binding component.² Approximately one-third of rivaroxaban is excreted by the kidneys unchanged while the remainder is metabolized in the liver. Approximately half of the inactive products formed via hepatic degradation are excreted via the kidneys and half via the hepatobiliary route. Significant renal impairment results in decreased clearance and increases overall exposure to the drug.⁹

The P-glycoprotein (P-gp) multidrug transporter protein facilitates the transport of rivaroxaban across cell membranes and influences the absorption and disposition of the drug in vivo.^3,6 Rivaroxaban is metabolized by the mixed function oxidase, cytochrome P450 3A4 (CYP3A4). Rivaroxaban has no major or active circulating metabolites.^3,6 Drugs that affect the activity of CYP3A4 and P-gp can potentially affect the pharmacokinetic profile of rivaroxaban.^3,6 Individuals with moderate hepatic impairment displayed increased and prolonged exposure with reduced total body clearance of rivaroxaban and increased inhibition of factor Xa compared with healthy individuals.⁹ Rivaroxaban is contraindicated in patients with significant hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk.^1,2 Rivaroxaban can be used with caution in cirrhotic patients with moderate hepatic impairment if it is not associated with coagulopathy and does not require dose adjustment in patients with other hepatic diseases.^1,2

Routine therapeutic monitoring of rivaroxaban level is not because of the drug's relatively wide therapeutic index. Despite the use of fixed doses of rivaroxaban, determination of the amount of drug present in a given individual may be valuable in several clinical situations. Measurement of levels can inform clinicians with concerns regarding patient compliance and adherence to therapy. Rivaroxaban is transported across the intestinal wall by P-gp and drugs that induce or inhibit P-gp activity, may decrease or increase the levels of rivaroxaban, respectively. Therapeutic monitoring can help the clinician assess the potential cause of bleeding or thrombosis while on therapy. Determination of levels may also be useful in preparation for surgery or an invasive procedure. Also, drug level measurement can be valuable in determining drug accumulation in situations of renal or hepatic failure and when administered with other drugs that may alter metabolism or clearance.

Rivaroxaban is measured using a validated liquid chromatography/mass spectrometry (LC/MS-MS) method. Use of liquid LC/MS-MS provides highly accurate measurement of rivaroxaban concentrations without the variable interferences associated with traditional clot-based and chromogenic assays.¹⁰ 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.