Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment,Clinical Pharmacokinetics

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Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-07-30 , DOI: 10.1007/s40262-022-01150-1
Vidya Perera ₁ , Grigor Abelian ₁ , Danshi Li ₁ , Zhaoqing Wang ₁ , Liping Zhang ₂ , Susan Lubin ₁ , Akintunde Bello ₁ , Bindu Murthy ₁

Affiliation

Objective

The aim of this study was to assess the effect of moderate or severe renal impairment on the pharmacokinetic (PK) properties of milvexian.

Methods

This open-label, parallel-group study assessed the PK, safety, and tolerability of a single oral 60 mg dose of milvexian in participants with normal renal function (n = 8; estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m²) and participants with moderate (n = 8; eGFR ≥ 30 to ≤ 59 mL/min/1.73 m²) or severe (n = 8; eGFR < 30 mL/min/1.73 m²) renal impairment. Regression analysis was performed using linear regression of log-transformed PK parameters versus eGFR.

Results

Milvexian was well tolerated, with no deaths, serious adverse events, or serious bleeding reported. The maximum milvexian concentration (C_max) was similar for all groups. Based on a regression analysis of milvexian concentration versus eGFR, participants with eGFR values of 30 and 15 mL/min/1.73 m², respectively, had area under the curve (AUC) values that were 41% and 54% greater than in participants with normal renal function. Median time to maximum concentration (T_max) was similar for the three groups (4.5–5.0 h). The half-life increased for participants with moderate (18.0 h) or severe (17.7 h) renal impairment compared with those with normal renal function (13.8 h).

Conclusion

A single dose of milvexian 60 mg was safe and well tolerated in participants with normal renal function and moderate or severe renal impairment. There was a similar increase in milvexian exposure between the moderate and severe renal groups.

Clinical Trials Registration

This study was registered with ClinicalTrials.gov (NCT03196206, first posted 22 June 2017).

中文翻译：

肾功能正常受试者和中度或重度肾损伤受试者中米尔维鲜的单剂量药代动力学

客观的

本研究的目的是评估中度或重度肾功能损害对 Milvexian 药代动力学 (PK) 特性的影响。

方法

这项开放标签、平行组研究评估了肾功能正常受试者（ n = 8；估计肾小球滤过率 [eGFR] ≥ 90 mL/min/ 1.73 m ² ）和中度（ n = 8；eGFR ≥ 30 至 ≤ 59 mL/min/1.73 m ² ）或重度（ n = 8；eGFR < 30 mL/min/1.73 m ² ）肾功能损害的参与者。使用对数转换的 PK 参数与 eGFR 的线性回归进行回归分析。

结果

Milvexian 的耐受性良好，没有死亡、严重不良事件或严重出血的报道。所有组的最大米尔维鲜浓度（ C _max ）相似。根据 Milvexian 浓度与 eGFR 的回归分析，eGFR 值分别为 30 和 15 mL/min/1.73 m ²的参与者的曲线下面积 (AUC) 值比 eGFR 值分别为 41% 和 54% 的参与者大肾功能正常。三组达到最大浓度的中位时间（ T _max ）相似（4.5-5.0 小时）。与肾功能正常的参与者（13.8 小时）相比，中度（18.0 小时）或重度（17.7 小时）肾功能不全的参与者的半衰期延长。