Orthopaedic Surgery and Traumatology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Pharmacology, Therapeutics and Toxicology, Universidad Autónoma de Barcelona, Bellaterra, Barcelona, Spain.
Clin Pharmacokinet. 2022 Jan;61(1):83-95. doi: 10.1007/s40262-021-01043-9. Epub 2021 Jul 13.
Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported.
The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment.
Patients who underwent primary unilateral total knee replacement (TKR) received 1 g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2 g (two doses of 1 g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance.
Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7 years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported.
This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8 h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA.
Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.
氨甲环酸（TXA）是一种抗纤维蛋白溶解药物，通常静脉内给药；然而，最近已经证明关节内给药与静脉内给药同样有效。关于关节内给药后 TXA 的药代动力学（PK）的信息有限。
本研究的目的是建立 TXA 单次关节内给药和两次静脉内给药的群体 PK 模型，并研究 TXA PK 过程中个体间变异性（IIV）的来源。所建立的模型用于模拟不同剂量方案和肾功能损害患者的 TXA PK 谱。
接受单侧初次全膝关节置换术（TKR）的患者在关闭伤口前直接将 1 g/10 mL（浓度为 100 mg/mL）的 TXA 应用于手术部位，或接受 2 g（两次 1 g）静脉内 TXA。使用非线性混合效应方法建立群体 PK 模型，并研究 IIV 的来源，如性别、年龄、体重、身高、体重指数（BMI）、术前血红蛋白、术前血细胞比容和肌酐清除率。
共纳入 24 例患者，每组 12 例。20 例患者为女性，平均年龄（标准差）为 73.7 岁（5.6）。TXA 的处置最好用具有依赖于肌酐清除率的清除的两室模型来描述。Bootstrap 结果表明该模型稳定且稳健。关节内给药的估计生物利用度为 81%。模拟结果表明，在本研究中使用的剂量和给药途径下，100%的患者在给药后 8 小时将具有与部分纤维蛋白溶解相关的血浆浓度。与静脉内给药相比，关节内给药仅能使 12%的患者完全抑制纤维蛋白溶解，而静脉内给药则能使 72.5%的患者完全抑制纤维蛋白溶解。未报告不良反应。
该群体 PK 模型表明，单次高浓度、低容量关节内 TXA 可达到药物 8 小时的抗纤维蛋白溶解血浆浓度，为接受 TKR 的患者提供局部和全身作用。TXA 给药至手术部位可能是 TKR 患者的替代静脉内给药途径；然而，需要临床研究来评估 TXA 的局部毒性作用。
西班牙临床研究登记号：2017-004059-22。注册日期：2018 年 4 月 12 日。
