Pharmacokinetics of Curative Tranexamic Acid in Parturients Undergoing Cesarean Delivery

Abstract

The aim of this study was to evaluate the population pharmacokinetics of tranexamic acid (TXA) administered intravenously at a single dose of 0.5 or 1 g in parturients undergoing active hemorrhagic cesarean delivery and to evaluate the influence of patient variables on TXA pharmacokinetics. Subjects from three recruiting centers were included in this PK sub-study if randomized in the experimental group (i.v TXA 0.5 g or 1 g over one minute) of the TRACES study. Blood samples and two urinary samples were collected within 6 h after TXA injection. Parametric non-linear mixed-effect modeling (Monolix v2020R1) was computed. The final covariate model building used 315 blood and 117 urinary concentrations from seventy-nine patients. A two-compartment model with a double first-order elimination from the central compartment best described the data. The population estimates of clearance (CL), central volume of distribution (V1), and half-life for a typical 70 kg patient with an estimated renal clearance of 150 mL/min (Cockroft–Gault) were 0.14 L/h, 9.25 L, and 1.8 h. A correlation between estimated creatinine clearance and CL, body weight before pregnancy, and V1 was found and partly explained the PK variability. The final model was internally validated using a 500-run bootstrap. The first population pharmacokinetic model of TXA in active hemorrhagic caesarean section was successfully developed and internally validated.

Tranexamic acid dose–response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study

“…The model was initially based on 53 data points from nine haemorrhagic patients in the TRACES pilot study and then consolidated by analysis of 385 blood samples and 117 urine samples from 79 patients. 10 , 11 , 26 A two-compartment model with dual (urinary and non-urinary) first-order excretion of TXA best predicted its plasma and urine concentrations. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Parametric non-linear mixed-effect modelling (Monolix 2020R1, Lixoft, Anthony, France) was computed.…”

“… 10 , 11 , 26 A two-compartment model with dual (urinary and non-urinary) first-order excretion of TXA best predicted its plasma and urine concentrations. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Parametric non-linear mixed-effect modelling (Monolix 2020R1, Lixoft, Anthony, France) was computed. Central compartment volume increased with body weight measured before pregnancy.…”

Fibrinolytic-deficiencies predispose hosts to septicemia from a catheter-associated UTI

“…Consistent with our CAUTI data, fibrin accumulation from imbalance between activation of coagulation and inhibition of fibrinolysis, is detrimental for patients suffering from COVID-19 59 and ventilator-associated pneumonia 60 . Moreover, fibrin accumulation can also result from antifibrinolytic treatments, which are commonly use in patients with bleeding disorders 58 , 61 (Supplementary Table 3 ), in patients with traumatic injuries, or undergoing surgical procedures that increase bleeding risk, including liver transplants, cardiac and cesarean surgeries 43 – 45 , 62 . TXA is an active inhibitor of uPA and tPA, and also plasmin-fibrin binding 63 , 64 .…”

Fibrinolytic-deficiencies predispose hosts to septicemia from a catheter-associated UTI.

“…Consistent with our CAUTI data, fibrin accumulation from imbalance between activation of coagulation and inhibition of fibrinolysis, is detrimental for patients suffering from COVID-19 56 and ventilator-associated pneumonia 57 . Moreover, fibrin accumulation can also result from antifibrinolytic treatments, which are commonly use in patients with bleeding disorders 55,58 (Table S3), in patients with traumatic injuries, or undergoing surgical procedures that increase bleeding risk, including liver transplants, cardiac and cesarean surgeries [41][42][43]59 . TXA is an active inhibitor of uPA and tPA, and also plasmin-fibrin binding 60,61 .…”