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.

Keywords: caesarean section; intravenous; pharmacokinetics; postpartum hemorrhage; tranexamic acid.

Figure A1

Individual weighted residuals (IWRES) plotted versus time (a) and tranexamic acid (TXA) blood concentrations. (c) Normalized prediction distribution errors (NPDE) plotted versus time (b) and TXA blood concentrations (d).

Figure 1

Hypothetical base models tested. The hypothetical tested parameters are represented in blue color.

Figure 2

Study flowchart. Legend: CS, caesarean section; TXA, tranexamic acid.

Figure 3

Base model result: two-compartment model with a double linear elimination (model A).

Figure 4

Correlations between the conditional mean of individual pharmacokinetic parameters and covariates of the final covariate model. Individual parameters are displayed by blue dots and regression line is displayed by the red line.

Figure 5

Goodness-of-fit plots obtained from the final covariate model: (A) The visual predictive check graph represents the observed plasma concentrations in tranexamic acid (TXA) plotted against time, based on 1000 Monte Carlo simulations. Prediction intervals for each percentile are estimated across all simulated data and represented as colored areas (pink for the 50th percentile, blue for the 10th and 90th percentiles). Observed data are displayed as blue dots. Predicted medians and empirical percentiles are displayed as green dotted lines and blue lines, respectively. (B) Normalized prediction distribution errors (NPDE) plotted against time and tranexamic acid (TXA) plasma concentrations. Observations plotted against populational (C) and individual (D) predicted tranexamic acid (TXA) plasma concentrations. Observations plotted against populational (E) and individual (F) predicted tranexamic acid (TXA) urinary concentrations. The limits of the 90% confidence intervals are displayed as green dotted lines. Concerning the VPC graph, curves representing empirical percentiles overlaid the prediction intervals. Concerning the observations versus predictions graph, the ratio of observed/predicted concentrations was around the x = y line for both plasma and urinary values. The proportions of plasma and urinary ratios that fell outside the 90% prediction interval were 2.2% and 6.8%, respectively. The distribution of NPDE was quite well adjusted to the density of the standard Gaussian distribution. The Shapiro–Wilk test of normality was significant, but significance is often observed when analyzing a large number of observations (Fc = 0.98, p-value = 5.8 × 10⁻⁵ for blood concentrations; Fc = 0.96, p-value = 4.84 × 10⁻⁴ for urinary concentrations) [14].

Figure 6

Monte Carlo simulations with the base model for 1000 individuals. Legend: (a) administration of a single dose of 1 g of tranexamic acid at T0; (b) administration of a single dose of 0.5 g of tranexamic acid at T0.

Figure 7

Representation of the mean resident time of TXA (A), the predicted maximal blood concentration of TXA (B), the blood concentration of tranexamic acid measured 30 min after the TXA administration (C), and the AUC estimated over the 30 min following the TXA administration (D) according to the groups of bleeding status defined 30 min after the first TXA injection. Legend: AUC, area under the curve; TXA, tranexamic acid.

Figure 8

Representation of the mean resident time of TXA (A), the predicted maximal blood concentration of TXA (B), the blood concentration of tranexamic acid measured 60 min after the TXA administration (C), and the AUC estimated over the 60 min following the TXA administration (D) according to the groups of bleeding status defined 60 min after the first TXA injection. Legend: AUC, area under the curve; TXA, tranexamic acid.