Assessment of Anti‐Xa activity in patients receiving concomitant apixaban with strong p‐glycoprotein inhibitors and statins

Abstract

What is known and objectives: Although the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p-glycoprotein (P-gp) and cytochrome P-450 (CYP) 3A4, there are limited published data regarding potential drug-drug interactions between apixaban (Eliquis) and common p-glycoprotein (P-gp) and CYP3A4 inhibitors co-administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co-administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin).Methods: Patients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40-64 and ≥65 years old) completing the observational study. Fifty-five volunteers were administered apixaban without the P-gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty-four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti-Xa assay.Results: Of the combinations studied, the mean apixaban trough concentration upon co-administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/− 79.59 ng/ml vs. control 104.09 +/− 44.56 ng/ ml; p = 0.04). The co-administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5-fold increase in apixaban concentrations (peak experimental 315.19 +/− 157.53 ng/ml vs control 207.6 +/− 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/− 95.93 ng/ml vs control 112.32 +/− 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak | 669 MILNER Et aL.

Does amiodarone impact on apixaban levels? The effect of amiodarone on apixaban level among Thai patients with non-valvular Atrial Fibrillation

“…The data reported from VigiBase, the World Health Organization database of spontaneous safety reports, showed that amiodarone has no significant effect on the AUC of apixaban [17]. Meanwhile, a previous observational study revealed that the apixaban trough concentration upon co-administration of amiodarone was elevated compared with apixaban alone [15]. In addition, Gulila M., et al showed that impaired-function variant ABCG2 c.421C > A, sex, and co-administration with amiodarone, which moderates the CYP3A4 and P-gp inhibitors, can be predictive of a high apixaban level [18].…”

“…After that, blood samples were collected into two 3.2% citrated tubes to measure both the trough and peak concentrations. The blood samples were centrifuged immediately for 15 mins at 2500-3000×g [14][15][16]21]. Apixaban plasma levels were measured by chromogenic assay, which were performed with the BIOPHEN TM heparin LRT kit (Hyphen BioMed, Neuville-sur-Oise, France) and analyzed by a Sysmex CS 2500 System (Siemens Health Care, Milan, Italy).…”

“…Therefore, the interaction between amiodarone and apixaban has been reported in caution. The data finding from the previous observational studies is controversial, some studies reported that clinical outcomes of amiodarone combined with apixaban did not increase the risk of stroke and major bleeding compared with warfarin, while other studies reported the apixaban levels only [15][16][17][18]. However, two large observational studies showed an increased risk of bleeding when using amiodarone with apixaban [19,20].…”

Do Apixaban Plasma Levels Relate to Bleeding? The Clinical Outcomes and Predictive Factors for Bleeding in Patients with Non-Valvular Atrial Fibrillation

“…However, the real-world pilot prospective study reported significantly higher C trough and C peak values in the bleeding group compared with the non-bleeding group [ 36 ], which is similar to our study. Concomitant with CYP3A4 and P-gp inhibitors, older age was a factor causing high apixaban plasma levels in the bleeding group [ 37 , 38 ]. Many reports demonstrated drug interactions and the effect of age on the apixaban levels [ 7 , 26 , 39 ].…”