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. 2021 Jan 30;22(1):45.
doi: 10.1186/s12882-021-02248-7.

Pharmacokinetics and dialytic clearance of apixaban during in vitro continuous renal replacement therapy

Lauren Andrews  1 , Scott Benken  1 , Xing Tan  1 , Eric Wenzler  2
Affiliations

Pharmacokinetics and dialytic clearance of apixaban during in vitro continuous renal replacement therapy

Lauren Andrews et al. BMC Nephrol. .

Abstract

Background: 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.

Methods: Apixaban 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.

Results: Mean 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.

Conclusion: For 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.

Keywords: Apixaban; CRRT; CVVH; CVVHD; Dialysis; Pharmacokinetics; Renal replacement therapy; Saturation coefficient; Sieving coefficient; Transmembrane clearance.

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Conflict of interest statement

E.W. serves on the speaker’s bureau for Allergan Plc, Melinta Therapeutics, and Astellas Pharma and on the advisory board for GenMark Diagnostics and Shionogi. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Pre-filter plasma concentration-time profiles of apixaban during CVVH and CVVHD at each rate and point of dilution with the HF1400 filter (a) and M150 filter (b). Mean values are displayed with error bars representing standard deviations
Fig. 2
Fig. 2
Mean CLTM by AUC of apixaban during CVVH at 2 L/h according to point of dilution and filter type. Bars represent mean values with 95% confidence intervals displayed as dashed lines
Fig. 3
Fig. 3
Mean CLTM by AUC of apixaban during in vitro CRRT according to mode, flow rate, and filter type. Bars represent mean values with 95% confidence intervals displayed as dashed lines
See this image and copyright information in PMC

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