Tranexamic dosing for major joint arthroplasty in adult patients with chronic kidney disease: A pharmacokinetic study and new dosing regimen.

Background: Tranexamic acid is an anti-fibrinolytic agent routinely used during hip and knee joint replacement surgery to minimize bleeding. Chronic kidney disease is a common chronic health problem seen among adults requiring major arthroplasty surgery. Tranexamic acid is renally cleared and may accumulate in chronic kidney disease. Optimal tranexamic acid dosing and dose adjustment for chronic kidney disease patients needing major arthroplasty is unknown. The objective of this study was to serially measure plasma tranexamic acid concentrations in patients with varied kidney function undergoing hip or knee replacement surgery for population pharmacokinetic modelling and to guide new dosing recommendations. Methods: Prospective cohort study enrolled 21 adults undergoing hip or knee replacement surgery between June 2020 – September 2022. Based on estimated glomerular filtration rate (eGFR), patients were stratified into good (≥ 60 mL/min/1.73 m 2 ) and poor (< 60 mL/min/1.73 m 2 ) renal function. Serial blood samples were taken to measure plasma tranexamic acid concentration levels (primary outcome) after an intravenous tranexamic acid 20 mg/kg bolus dose post anesthesia induction. Secondary clinical outcomes included adverse events (thromboembolic events, seizures), red cell transfusion, mortality, length of hospital stay. Analyses used curve stripping and population pharmacokinetic modelling and simulation. Results: Plasma tranexamic acid concentration levels were higher in patients with poor renal function and clearance compared to good renal function. Population pharmacokinetic modelling tested various tranexamic acid bolus and maintenance infusion regimens. Simulations revealed single bolus tranexamic acid administration leads to rapid rise and decline in plasma concentrations. We identified that plasma tranexamic acid levels of 50-75 mg/L were maintained for approximately 4 hours using a tranexamic acid bolus infusion of 15 mg/kg over 15 min together with a maintenance infusion of 7.5 mg/kg/h or 5 mg/kg/h for 2 hours for the good and poor renal function groups, respectively. There was no difference in secondary outcomes. Conclusion: Using population pharmacokinetic modelling and simulation, we recommend a new dosing regimen to optimize the anti-fibrinolytic effect of tranexamic acid and avoid excessive dosing.