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

Abstract

Uncertainty about optimal tranexamic acid (TXA) dosage has led to significant practice variation in hip arthroplasty. We aimed to identify the optimal intravenous dosage of TXA using a population pharmacokinetic/pharmacodynamic (PK/PD) approach in adults undergoing primary elective hip arthroplasty. 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. 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 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 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. The PK/PD modelling indicated that a 15 mg kg^-1 i.v. TXA bolus followed by a continuous i.v. infusion achieved the 24-h antifibrinolytic target. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377339&isClinicalTrial=False (ACTRN12619000670178); registered on May 6, 2019.