A pharmacokinetic/pharmacodynamic analysis of intravenous tranexamic acid in adult patients undergoing elective total hip arthroplasty (ORACLE)

Background: Uncertainty about optimal tranexamic acid (TXA) dosage has led to significant practice variation in hip arthroplasty. We aimed to identify the optimal i.v. dosage of TXA using a population pharmacokinetic/pharmacodynamic (PK/PD) approach in adults undergoing primary elective hip arthroplasty.

Methods: Participants received an i.v. TXA bolus dose of 15 mg kg^-1 of total body weight, 30 min before skin incision (maximum dose 1500 mg). Blood samples were collected at baseline, 5 min post-TXA, skin incision, skin closure, and 3, 6, and 24 h post-TXA administration. TXA activity was measured ex vivo using a tissue plasminogen activator-induced clot lysis assay, targeted to achieve 90% maximal antifibrinolysis, based on maximum lysis rate. A nonlinear mixed-effects population PK/PD model was developed. Monte Carlo simulations (n=1000) identified the dosing regimens to achieve the PK/PD target over 24 h.

Results: There were 24 participants (18 females, 6 males), with a median (range) age of 62 (56.5-72) yr and BMI of 31.1 (23.0-41.8) kg m^-2. A three-compartment model best described the 24-h data. The 15 mg kg^-1 of i.v. bolus maintained TXA concentrations above the PK/PD target of 10 mg L^-1 for a median duration of 4.94 h (IQR: 3.76-8.21 h). Of the various simulated regimens, only 30 mg kg^-1 of i.v. TXA infusion after this bolus achieved the 24-h PK/PD target in 76-100% of patients, varying with their estimated glomerular function rates.

Conclusions: The PK/PD modelling indicated that 15 mg kg^-1 of i.v. TXA bolus followed by a continuous i.v. infusion achieves the 24-h antifibrinolytic target.

Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377339&isClinicalTrial=False (ACTRN12619000670178); registered on May 6, 2019.