Background

In response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration.

Methods

We conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography–mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics.

Results

The median time to reach a concentration of 10 mg L⁻¹ was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L⁻¹ for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h⁻¹ for elimination clearance, 15.6 L h⁻¹ for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain.

Conclusions

The i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics.

Clinical trial registration

EudraCT 2019-000285-38; NCT 03777488.

中文翻译：

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氨甲环酸在静脉、肌肉和口服途径后的药代动力学：一项在健康志愿者中进行的前瞻性、随机、交叉试验

背景

为响应世界卫生组织呼吁对产后出血妇女使用氨甲环酸 (TXA) 的替代给药途径进行研究，我们检测了静脉内、肌内或口服给药后 TXA 的药代动力学。

方法

我们对 15 名接受 iv TXA 1 g、im TXA 1 g 或口服 TXA 溶液 2 g 的健康志愿者进行了一项随机、开放标签、交叉试验。在给药后 24 小时抽取血样。采用液相色谱-质谱法测量氨甲环酸浓度，并使用群体药代动力学估计药代动力学模型的参数。

结果

达到 10 mg L ^-1浓度的中位时间对于 im 途径为 3.5 分钟，对于口服途径为 66 分钟，尽管通过口服途径仅在 11 名患者中达到目标浓度。iv、im 和口服途径的中位峰浓度分别为 57.5、34.4 和 12.8 mg L ^{-1 。}以体重为主要协变量的两室开放模型最适合数据。对于 70 kg 的志愿者，人口估计为 10.1 L h ^-1用于消除清除，15.6 L h ^-1对于室间间隙，中央室容积为 7.7 L，外围室容积为 10.8 L。肌内和口服生物利用度分别为 1.0 和 0.47，表明肌内吸收快速且完全。不良事件轻微且短暂，主要为局部反应和低强度疼痛。

结论

im（但不是口服）途径似乎是 iv 氨甲环酸的有效替代方案。需要对孕妇进行研究以检查妊娠对药代动力学的影响。

临床试验注册

EudraCT 2019-000285-38；NCT 03777488。