College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 164 (M/C 886),, Chicago, IL, 60612, USA.
BMC Nephrol. 2021 Jan 30;22(1):45. doi: 10.1186/s12882-021-02248-7.
To evaluate the transmembrane clearance (CL) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations.
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. CL 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 CL 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.
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 CL was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CL values calculated by AUC were used (adjusted R 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 CL 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.
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.
评估模型体外连续肾脏替代治疗（CRRT）期间阿哌沙班的跨膜清除率（CL），评估蛋白结合和回路吸附，并提供初始给药建议。
将阿哌沙班加入 CRRT 回路中，并沿预滤器牛血样收集后滤器血和流出物样本。使用连续静脉-静脉血液滤过（CVVH）和血液透析（CVVHD）模式，使用不同的滤器类型、流速和 CVVH 置换液稀释点，重复进行所有实验。通过液相色谱-串联质谱法定量阿哌沙班和尿素的浓度。通过非房室分析估算阿哌沙班的血浆药代动力学参数。通过估计的曲线下面积（AUC）和筛分/饱和系数（SC/SA）与流速的乘积计算 CL。建立二项式和三项式方差（ANOVA）模型，通过每种方法评估模式、滤器类型、流速和稀释点对 CL 的影响。通过将体外观察到的 AUC 与阿哌沙班 2/3 期研究中观察到的全身暴露相匹配，建议最佳剂量。利用线性回归为 0.5-5 L/h 的流速提供剂量估算。
HF1400 和 M150 过滤器的平均吸附率分别显著差异 38%和 13%，而平均（±标准偏差，SD）蛋白结合百分比为 70.81±0.01%。CVVH 稀释点的影响在不同滤器类型之间没有差异，尽管在使用 HF1400 过滤器的 CRRT 期间，CL 始终明显高于 M150。三项式 ANOVA 表明，当使用 AUC 计算的 CL 值时，拟合度更好（调整后的 R 0.87 与 0.52），因此，使用这些值生成最佳给药建议。线性回归显示，AUC 的 CL 受滤器类型和流速的显著影响，提示对于分别为 0.5-5 L/h 的流速，可能需要 2.5-7.5mg 每日两次（BID）的剂量。
对于临床上最常用的 CRRT 流速，预计标准标记的 5mg BID 剂量的阿哌沙班将达到目标全身暴露阈值。这些建议的给药方案的安全性和有效性需要进一步的临床研究。
