Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment

Abstract

Tranexamic acid (TXA), an effective anti‐fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter‐patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re‐examined with a two‐compartment model using the ADAPT5® and NONMEMVII® to identify covariates that explain inter‐patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two‐compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg·L−1). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB. Copyright © 2015 John Wiley & Sons, Ltd.

Tranexamic acid through intravenous, intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

“…The red line represents the mean and the light blue areas the 95% confidence interval. pharmacokinetics [12][13][14][29][30][31]. Attempts with 1compartment models always provided models with poorer performance than two-compartment models.…”

Manifestation of tranexamic acid toxicity in chronic kidney disease and kidney transplant patients: A report of four cases and review of literature

“…recently reviewed these two regimes using simulations based on a two‐compartmental model and showed that the regime proposed by Fergusson et al . resulted in much higher predicted TXA concentrations in patients with moderate to severe CKD . The investigators suggested to reduce the maintenance dose of TXA according to patients’ renal function while keeping the same loading dose.…”

Tranexamic acid: a clinical review

“…Approximately 95% of TXA is excreted via the urine unchanged, and excretion decreases with increasing plasma creatinine levels. The dosage adjustment for renal-impaired patients remains an unknown; Jang et al [151]used the 2 compartment model to guide a simulated reduction of the maintenance infusion rate according to the GFR of patients during CPB to achieve > 100 μg mL -1 threshold plasma concentrations. Please see full paper, which just got published.…”