Dunn Allison, Felfeli Mina, Seifert Sebastian M, Gilliot Sixtine, Ducloy-Bouthors Anne-Sophie, Shakur-Still Haleem, Geer Amber, Grassin-Delyle Stanislas, Luban Naomi L, van den Anker Johannes N, Gobburu Jogarao V S, Roberts Ian, Ahmadzia Homa K
Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD, USA.
Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
J Clin Pharmacol. 2025 May 19. doi: 10.1002/jcph.70031.
Tranexamic acid (TXA) is used for the treatment and occasionally prevention of postpartum hemorrhage (PPH); however, questions still remain regarding dosing regimen optimization. This study evaluated TXA pharmacokinetic (PK) data from four clinical trials (NCT: 04274335, 03287336, 00872469, and 02797119) conducted in pregnant participants receiving intravenous, intramuscular, or oral TXA to prevent or treat PPH. The goal of this analysis was to comprehensively characterize TXA PK in a large, heterogeneous population of pregnant individuals to (1) assess the need for weight-based dosing and (2) compare exposure target attainment for alternative routes of administration. A population PK analysis was performed using nonlinear mixed-effects modeling in Pumas, and a stepwise approach was implemented to select the structural model and identify significant covariates. A total of 211 pregnant participants who received between 0.35 and 4 g of TXA intravenously, orally, or intramuscularly offered 1303 TXA plasma concentrations for model development. A two-compartment model with first-order elimination and first-order absorption for both intramuscular and oral administration best described the disposition of TXA. Actual body weight was the only statistically significant covariate identified, but inclusion into the model did not explain a substantial amount of the observed variability. Simulations of virtual pregnant individuals indicated minimal differences in TXA exposure between fixed and weight-based dosing regimens, supporting the use of fixed dosing. Intramuscular TXA was additionally found to be a viable alternative to intravenous administration, achieving similar target exposure metrics.
氨甲环酸（TXA）用于治疗产后出血（PPH），偶尔也用于预防；然而，在给药方案优化方面仍存在问题。本研究评估了四项临床试验（NCT：04274335、03287336、00872469和02797119）中的TXA药代动力学（PK）数据，这些试验在接受静脉、肌肉或口服TXA以预防或治疗PPH的孕妇中进行。该分析的目的是全面描述大量异质性孕妇群体中的TXA PK，以（1）评估基于体重给药的必要性，以及（2）比较不同给药途径的暴露目标达成情况。使用Pumas中的非线性混合效应模型进行群体PK分析，并采用逐步方法选择结构模型并识别显著协变量。共有211名孕妇接受了0.35至4 g的静脉、口服或肌肉注射TXA，提供了1303个TXA血浆浓度用于模型开发。一个具有一级消除和一级吸收的两室模型最能描述肌肉注射和口服给药时TXA的处置情况。实际体重是唯一确定的具有统计学意义的协变量，但将其纳入模型并不能解释大量观察到的变异性。虚拟孕妇的模拟表明，固定剂量和基于体重的给药方案之间TXA暴露差异最小，支持使用固定剂量。此外，发现肌肉注射TXA是静脉注射的可行替代方法，可实现类似的目标暴露指标。
