Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial

Abstract

Background: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. Methods: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0$5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixedeffect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. Results: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h À1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h À1 for elimination clearance, 11.7 L h À1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L À1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. Conclusions: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. Clinical trial registration: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).

Clinical Validation of a Volumetric Absorptive Micro-Sampling Device for Pharmacokinetic Studies With Tranexamic Acid

“…However, the “translation” of whole blood TXA levels from VAMS capillary samples into plasma levels may require caution for high concentrations. The concentration range of the present study was less than 40 mg/L, corresponding to concentrations observed in pharmacokinetic studies with an intramuscular dose of 1 g or an oral dose of 2 g ( Grassin-Delyle et al, 2021a ; Grassin-Delyle et al, 2021b ). These pharmacokinetic studies with outpatient TXA use are precisely the types of studies for which design is most appropriate for the use of VAMS devices.…”

“…Although tranexamic acid (TXA) has been marketed for the prevention of bleeding since the 1960s and has been used in a range of surgical and out-of-hospital indications, the dosing regimens used are mostly empirical. High quality clinical trials with sufficient power to support efficacy in acute severe bleeding are relatively recent, as are the pharmacokinetic studies ( Collaborators, 2019 ; Collaborators et al, 2010 ; Woman Trial Collaborators, 2017 ; Grassin-Delyle et al, 2021a ; Grassin-Delyle et al, 2021b ; Grassin-Delyle et al, 2018 ; Grassin-Delyle et al, 2013a ). Timely TXA treatment, ideally within an hour of bleeding onset, has been shown to be essential for maximal efficacy in acute severe bleeding and so effective TXA blood concentrations must be achieved rapidly ( Collaborators et al, 2011 ; Gayet-Ageron et al, 2018 ).…”

Tranexamic Acid Treatment for Trauma Victims

“…A recent prospective, pharmacokinetic study conducted in the emergency departments of two large London trauma centers has shown that intramuscular (IM) TXA is well tolerated and rapidly absorbed in bleeding trauma patients. 24 In this study, adult trauma patients who had received an IV 1-g TXA loading dose, either prehospital or in-hospital, were given the second TXA dose by IM injection. The IM dose was given as two 5 mL (0.5 g each) injections into the thigh (rectus femoris or vastus lateralis), gluteal, or deltoid muscles, depending on the clinical situation (e.g., the type of injury).…”

Validation of the BATT score for prehospital risk stratification of traumatic haemorrhagic death: Usefulness for tranexamic acid treatment criteria.

“…[25,34] Recent research has found that TXA is well tolerated and rapidly absorbed after intramuscular injection reaching therapeutic concentrations within 15 minutes in bleeding trauma patients. [35] Further research is needed to assess the cost-effectiveness of different treatment thresholds and whether use of the BATT score and intramuscular TXA administration by paramedics increases the pre-hospital administration of TXA to patients at risk of bleeding from trauma. Prospective validation of the BATT score would certainly increase its value for clinical use.…”