title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada, M5S 3M2.
authors.forename: Qi Joy
authors.initials: QJ
authors.lastname: Yang
authors.affiliation: Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada, M5G 2C4.
authors.forename: Angela
authors.initials: A
authors.lastname: Jerath
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Clinical and Translational Sciences Institute, Indianapolis, IN, 46202, USA.|Centre for Addiction and Mental Health, Program in Geriatric Psychopharmacology, Toronto, Ontario, Canada.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.affiliation: Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada, M5G 2C4.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wąsowicz
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada, M5S 3M2.
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
mesh_terms: D000368:Aged; D000933:Antifibrinolytic Agents / Q000493:pharmacokinetics*; D002315:Cardiopulmonary Bypass; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D051437:Renal Insufficiency / Q000378:metabolism*; D014148:Tranexamic Acid / Q000493:pharmacokinetics*
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid
keywords: BART dose; cardiopulmonary bypass; creatinine clearance; dose optimization; glomerular filtration; pharmacokinetic or population modeling; renal clearance; renal dysfunction; tranexamic acid