Population pharmacokinetics and pharmacodynamics of Tranexamic acid in women undergoing caesarean delivery

Abstract

Aims: The population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies.

Methods: We analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15 mg/kg of TXA intravenously using population approach.

Results: TXA PK was best described by a two-compartment model with first-order elimination and the following parameters: clearance (between-subject variability) of 9.4 L/h (27.7%), central volume of 10.1 L (47.4%), intercompartmental clearance of 22.4 L/h (66.7%), peripheral volume of 14.0 L (13.1%) and additive error of 1.4 mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC₅₀ of 6.0 mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650 mg of TXA maintained therapeutic targets for 30 minutes and 1 hour, respectively, in 90% of patients.

Conclusion: This is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650 mg dose provides adequate PPH prophylaxis up to 1 hour, which is less than the currently used 1000 mg of TXA in pregnant women.

Keywords: TXA; population pharmacodynamics; population pharmacokinetics; post-partum haemorrhage; prophylaxis.

Figure 1. PK exploratory profiles

Individual dose-normalized concentration-time profiles with geometric mean profiles for each dose cohort (5mg/kg: red; 10 mg/kg: green; 15 mg/kg: blue) in semi-logarithm scale for the whole PK assessment (A) and the first eight hours after administration (B). All concentrations were normalized to 70 kg using actual concentration divided by dose (in mg) and then multiplied by 350 mg (for 5 mg/kg cohort) or 700 mg (for 10 mg/kg cohort) or 1000 mg (for 15 mg/kg cohort).

Figure 2. PD exploratory profiles

(A)Individual maximum lysis-time profiles with geometric mean profiles for each cohort (5mg/kg: red; 10 mg/kg: green; 15 mg/kg: blue). (B) Individual maximum lysis -concentration profiles with geometric mean profiles for each cohort (5mg/kg: red; 10 mg/kg: green; 15 mg/kg: blue).

Figure 3. Goodness of fit plots for PK and PD models

Observations with predictions for PK and PD models (PK: A, PD: B). Black solid lines are identity lines. Individual PK and PD profiles (PK: C, PD: D) for patients with lowest, median and highest body weight and age, respectively. Symbols are the observation and dashed red lines are prediction.

Figure 4. Proportion of patients to reach targets

Proportional of the 30 patients reach the PK target (red) and PD target (blue) for 0.5 hour and 1 hour after the administration of TXA doses of 100 mg to 1000 mg.