Abstract
BackgroundTo evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations.MethodsApixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was utilized to provide dosing estimations for flow rates from 0.5–5 L/h.ResultsMean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81 ± 0.01%. Effect of CVVH point of dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 2.5–7.5 mg twice daily (BID) may be needed for flow rates ranging from 0.5–5 L/h, respectively.ConclusionFor CRRT flow rates most commonly employed in clinical practice, the standard labeled 5 mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.
Highlights
To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations
The blood flow rate was fixed at 200 mL/min for all experiments while continuous venovenous hemofiltration (CVVH) replacement fluid (PrismaSOL® BGK 2/0; Baxter Healthcare Corporation, Deerfield, IL, USA) and CVVH D dialysate (PrismaSATE® BGK 2/0; Baxter Healthcare Corporation, Deerfield, IL, USA) rates of 2 L/h and 4 L/h were tested with each filter type
As recognized by the Food and Drug Administration (FDA), National Institutes of Health (NIH), and National Institute of Allergy and Infectious Diseases (NIAID), nonclinical PK/PD models play a critical role in designing human dosage regimens and are essential tools for drug development and dose optimization in special populations [43]
Summary
To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. Parenteral anticoagulation with unfractionated heparin (UFH) is the current mainstay therapy for VTE and NOAF in this population given its rapid onset of action and short half-life [8]. In the critically ill ICU population, only approximately 50% of patients achieve therapeutic aPTTs within this same time frame, largely secondary to pathophysiologic and pharmacokinetic (PK) derangements such as sepsis-induced acute kidney injury (AKI), which can necessitate renal replacement therapy (RRT) in up to 70% of patients [13,14,15,16,17,18,19,20,21]. Given the challenges in optimizing the use of UFH and LMWH in the ICU setting, more reliable anticoagulation therapies are desperately needed for managing critically ill patients, especially those requiring extracorporeal organ support such as continuous RRT (CRRT)
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