Aránzazu González Osuna1, Luisa Fernanda Rojas2, Claudia Lamas1,3, Xavier Aguilera Roig1,3, Francesc Pla-Junca2, Sebastián Videla4,5, Mª José Martínez-Zapata6, Marta Valle2. 1. Orthopaedic Surgery and Traumatology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 2. Department of Pharmacology, Therapeutics and Toxicology, Universidad Autónoma de Barcelona, Bellaterra, Barcelona, Spain. 3. Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain. 4. Clinical Research Support Unit, Clinical Pharmacology Department, Bellvitge University Hospital/Bellvitge Biomedical Research Institute (IDIBELL), Carrer de la Feixa Llarga, s/n, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. svidela@bellvitgehospital.cat. 5. Department of Pathology and Experimental Therapeutics, Faculty of Medicine, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. svidela@bellvitgehospital.cat. 6. Iberoamerican Cochrane Centre-Public Health and Clinical Epidemiology, IIBSant Pau, CIBERESP, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Mª Claret, 165, 08025, Barcelona, Spain. mmartinezz@santpau.cat.
Abstract
BACKGROUND: Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported. AIMS: The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment. METHODS: Patients who underwent primary unilateral total knee replacement (TKR) received 1 g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2 g (two doses of 1 g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance. RESULTS: Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7 years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported. CONCLUSIONS: This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8 h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA. TRIAL REGISTRATION: Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.
BACKGROUND: Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported. AIMS: The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment. METHODS: Patients who underwent primary unilateral total knee replacement (TKR) received 1 g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2 g (two doses of 1 g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance. RESULTS: Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7 years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported. CONCLUSIONS: This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8 h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA. TRIAL REGISTRATION: Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.
Authors: Roberto Picetti; Haleema Shakur-Still; Robert L Medcalf; Joseph F Standing; Ian Roberts Journal: Blood Coagul Fibrinolysis Date: 2019-01 Impact factor: 1.276
Authors: Antonio Benjumea; Marta Díaz-Navarro; Rama Hafian; Emilia Cercenado; Mar Sánchez-Somolinos; Javier Vaquero; Francisco Chana; Patricia Muñoz; María Guembe Journal: Front Microbiol Date: 2022-06-30 Impact factor: 6.064