Plasma Tranexamic Acid Concentrations Research Articles

Pharmacokinetic Studies in Women of 2 Novel Oral Formulations of Tranexamic Acid Therapy for Heavy Menstrual Bleeding

Two randomized, open-label clinical studies involving healthy female volunteers aged 18-45 years (study 1, N = 32; study 2, N = 40) are described, which characterize the pharmacokinetics and steady-state dosage regimen performance of 2 novel, modified-release tranexamic acid tablet formulations. The objective of these studies was to identify the optimum product formulation to advance into late-phase clinical trials for heavy menstrual bleeding. For study 1, participants received single 1.3-g doses (2 650-mg tablets) of tranexamic acid modified-immediate-release (MIR) and tranexamic acid delayed-release (DR) formulations under fasting conditions compared with nonfasting conditions (after breakfast). For study 2, participants received tranexamic acid MIR or tranexamic acid DR as a single 1.3-g dose followed by a dosage regimen of 1.3 g every 8 hours for 5 days. Plasma tranexamic acid concentrations reached minimum effective levels (≥5 μg/mL) within 1.5 hours and within 3 hours after a 1.3-g tranexamic acid MIR and tranexamic acid DR dose, respectively. Food did not appreciably influence tranexamic acid MIR pharmacokinetics, whereas a high-fat meal significantly lowered the maximum concentration produced with tranexamic acid DR. Peak systemic exposure and maintenance of plasma tranexamic acid concentrations within the therapeutic range (5-15 μg/mL) were optimally achieved with 1.3 g of the MIR formulation dosed every 8 hours. The MIR and DR formulations were well tolerated. Peak-to-trough steady-state performance of the tranexamic acid MIR 1.3-g product (dosed every 8 hours, or 3 times daily, for up to 5 days) supported its advancement to late-phase clinical trials in women with heavy menstrual bleeding.

Efficacy of Tranexamic Acid in Pediatric Craniosynostosis Surgery

Background: Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. Methods: Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg ―1 , followed by an infusion of 5 mg·kg ―1 ·h ―1 during surgery. TXA plasma concentrations were measured. Results: The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg ―1 , P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg ―1 , P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg ―1 (95% CI for the difference, 23-84 ml·kg ―1 ) and for packed erythrocytes transfused was 23 ml·kg ―1 (95% CI for the difference, 7-39 ml·kg ―1 ). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 μg·ml ―1 ) and plasmin-induced platelet activation (16 μg·ml ―1 ) throughout the infusion. Conclusions: TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Use of a novel technique, solid phase microextraction, to measure tranexamic acid in patients undergoing cardiac surgery

Solid phase microextraction (SPME) is a technique widely used and accepted in the field of food technology and in environmental and biological analyses. Despite its numerous advantages over older analytical methods, it has not been studied extensively in the medical sciences. Tranexamic acid (TXA) is currently the sole antifibrinolytic agent used during cardiac surgery involving the use of cardiopulmonary bypass (CPB). The current standard method of measuring TXA in plasma is based on plasma protein precipitation (PPP), but this analytical approach is time-consuming and not practical for routine use. The aim of the current study was to compare plasma TXA levels measured with the PPP method vs those acquired with the novel, highly efficient SPME technique. We also investigated the use of automated SPME with the aim of improving the technique so it could be used efficiently for measuring plasma TXA levels. With Research Ethics Board approval, we undertook a prospective, investigator-blinded study in ten patients undergoing cardiac surgery with CPB. An initial TXA bolus of 30mg·kg(-1) was infused over 15min followed by a 16mg·kg(-1)·hr(-1) infusion until chest closure with a 2mg·kg(-1) load in the pump prime. Each blood sample was divided into two portions and assigned a random number to blind the analyzing laboratory. The blood TXA concentration was measured using both PPP and SPME. Agreement between the two tests was analyzed using the Bland-Altman plot. Comparisons of plasma TXA concentrations measured with the two methods (PPP and SPME) showed good agreement. Absolute recovery of TXA for PPP was 64.9-78.2%; its precision, as a percentage of the relative standard deviation (RSD) was < 10% [with the exception of the lower limit of quantification (LLOQ), where the RSD was 18%]; and its accuracy, as the bias against the nominal concentration, was < 7% (for LLOQ it was 15%). Thus, extraction with SPME compared favourably with the PPP technique. Solid phase microextraction is a relatively simple, rapid extraction technique that can facilitate future pharmacokinetic studies analyzing TXA drug concentrations and drug dosing in various clinical settings.

Efficacy of Tranexamic Acid in Pediatric Craniosynostosis Surgery

Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg(-1), followed by an infusion of 5 mg·kg·h(-1) during surgery. TXA plasma concentrations were measured. The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg(-1), P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg(-1), P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg(-1) (95% CI for the difference, 23-84 ml·kg(-1)) and for packed erythrocytes transfused was 23 ml·kg(-1) (95% CI for the difference, 7-39 ml·kg(-1)). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 μg·ml(-1)) and plasmin-induced platelet activation (16 μg·ml(-1)) throughout the infusion. TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Thorough cardiac QTc interval conductance assessment of a novel oral tranexamic acid treatment for heavy menstrual bleeding

Objective: To assess the effect of a novel oral tranexamic acid treatment on cardiac repolarization in a randomized, double-blind, positive- and placebo-controlled, four-treatment single-dose cross-over inpatient study.Methods: QTc interval and drug exposure relationship analyses were performed using triplicate digital electrocardiographs (ECGs) collected from 12-lead Holter monitors from healthy females (n = 48) with plasma drug concentrations and pharmacokinetics simultaneously evaluated over 24 h post-dose. Therapeutic (1.3 g) and supratherapeutic (3.9 g) tranexamic acid modified immediate-release doses, a positive-control 0.4 g moxifloxacin dose, and a placebo-control were administered at each period.Results: All post-dose, time-matched, baseline-adjusted, mean QTcF (Fridericia's heart rate correction, QT/RR1/3) treatment-placebo differences (ΔΔQTcF), were less than 5 milliseconds (ms) for the 1.3 g and 3.9 g tranexamic acid doses. Upper limits of the 95% confidence interval (CI) for all tranexamic acid-placebo ΔΔQTcF doses were < 10 ms for all time points. Lower limits of the 95% CI for the positive-control (moxifloxacin-placebo) ΔΔQTcF were > 5 ms at multiple time points demonstrating assay sensitivity. No correlation between tranexamic acid plasma concentrations and adjusted QTc intervals was observed. A positive linear relationship was observed for moxifloxacin (p < 0.01).Conclusion: Cardiac repolarization is not influenced by tranexamic acid at the doses studied.

A Preliminary Study of a New Tranexamic Acid Dosing Schedule for Cardiac Surgery

The authors have developed an alternative dosing schedule for tranexamic acid that incorporates the effects of renal function on tranexamic acid concentrations. The objectives of this study were to determine if this new dosing schedule can achieve the desired plasma concentration of tranexamic acid and reduce intra- and interpatient variability in tranexamic acid plasma concentrations relative to the current dosing schedule. A prospective randomized trial. A tertiary referral medical center hospital. Cardiac surgery patients. Cardiac surgery patients were randomly assigned to receive the authors' standard tranexamic acid loading dosage of 10 mg/kg given over 20 minutes, followed by an infusion of 1 mg/kg/h (9 patients), or the new drug dosage schedule described later (11 patients). Perioperative plasma tranexamic acid concentrations were measured using high-performance liquid chromatography. From repeated-measures analysis of variance, a significant (p < 0.001) time-by-treatment interaction effect was detected indicating that differences in mean tranexamic acid concentration between treatment groups were dependent on time period. Among patients receiving the standard dosing regimen, those with renal insufficiency had lower tranexamic acid concentration at 5 minutes on cardiopulmonary bypass (p = 0.003). For patients receiving the experimental regimen, the mean tranexamic acid concentration did not differ significantly at any time point between patients with and without renal insufficiency (p > 0.20 at all time points). The new dosing protocol for tranexamic acid resulted in more consistent blood concentrations of tranexamic acid, but not stable tranexamic acid levels >20 microg/mL on cardiopulmonary bypass.

Plasma Tranexamic Acid Concentrations During Cardiopulmonary Bypass

Although tranexamic acid is used to reduce bleeding after cardiac surgery, there is large variation in the recommended dose, and few studies of plasma concentrations of the drug during cardiopulmonary bypass (CPB) have been performed. The plasma tranexamic acid concentration reported to inhibit fibrinolysis in vitro is 10 microg/mL. Twenty-one patients received an initial dose of 10 mg/kg given over 20 min followed by an infusion of 1 mg. kg(-1). h(-1) via a central venous catheter. Two patients were removed from the study secondary to protocol violation. Perioperative plasma tranexamic acid concentrations were measured with high-performance liquid chromatography. Plasma tranexamic acid concentrations (microg/mL; mean +/- SD [95% confidence interval]) were 37.4 +/- 16.9 (45.5, 29.3) after bolus, 27.6 +/- 7.9 (31.4, 23.8) after 5 min on CPB, 31.4 +/- 12.1 (37.2, 25.6) after 30 min on CPB, 29.2 +/- 9.0 (34.6, 23.8) after 60 min on CPB, 25.6 +/- 18.6 (35.1, 16.1) at discontinuation of tranexamic acid infusion, and 17.7 +/- 13.1 (24.1, 11.1) 1 h after discontinuation of tranexamic acid infusion. Four patients with renal insufficiency had increased concentrations of tranexamic acid at discontinuation of the drug. Repeated-measures analysis revealed a significant main effect of abnormal creatinine concentration (P = 0.02) and time (P < 0.001) on plasma tranexamic acid concentration and a significant time x creatinine concentration interaction (P < 0.001). A 10 mg/kg initial dose of tranexamic acid followed by an infusion of 1 mg.kg(-1).h(-1)produced plasma concentrations throughout the cardiopulmonary bypass period sufficient to inhibit fibrinolysis in vitro. The dosing of tranexamic acid may require adjustment for renal insufficiency.

Application of Pharmacokinetic Data from Healthy Volunteers for the Prediction of Plasma Concentrations of Tranexamic Acid in Surgical Patients

The aim of this study was to investigate whether plasma concentrations of tranexamic acid in surgical patients during total hip replacement can be predicted from pharmacokinetic data from healthy volunteers, and whether therapeutic concentrations are sustained during the period of postoperative bleeding. Ten patients with normal kidney function received 10 mg/kg of tranexamic acid intravenously before surgery and another 10 mg/kg 3 hours later. Plasma concentration curves of tranexamic acid were computer-simulated, based on pharmacokinetic data from a volunteer study. Plasma concentrations in the patients were determined repeatedly and compared with the predicted values. Glomerular filtration rate was determined peroperatively as iohexol clearance. The blood loss was determined per- and postoperatively. The actual plasma concentrations of tranexamic acid were as predicted, or above, in all but two patients. These two were the youngest in the study, with the highest iohexol clearance; in both cases haemodilution was carried out and in one blood recovery with a cell saver was also used during surgery. A therapeutic level (> 10 mg/L) of tranexamic acid was maintained for approximately 8 hours, i.e. during the period of major bleeding. The plasma concentrations of tranexamic acid in surgical patients with normal kidney function can consequently be predicted from studies in healthy volunteers. Targeting of a therapeutic plasma concentration for the desired period of time is thus possible and can form the basis for a rational dosing of tranexamic acid.

Determination of plasma tranexamic acid using cation-exchange high-performance liquid chromatography with fluorescence detection

A procedure is described for the determination of plasma tranexamic acid concentrations using cation exchange high-performance liquid chromatography with fluorescence detection following post-column derivatisation with o-phthalaldehyde. The chromatographic conditions were optimised with respect to detector performance and the method applied to measuring the plasma tranexamic acid levels of patients in a double-blind trial.