Stanislas Grassin-Delyle1, Haleema Shakur-Still2, Roberto Picetti2, Lauren Frimley2, Heather Jarman3, Ross Davenport4, William McGuinness3, Phil Moss3, Jason Pott4, Nigel Tai4, Elodie Lamy5, Saïk Urien6, Danielle Prowse2, Andrew Thayne2, Catherine Gilliam2, Harvey Pynn7, Ian Roberts8. 1. Département de Biotechnologie de la Santé, Université Paris-Saclay, UVSQ, Inserm, Infection et inflammation, Montigny le Bretonneux, France; Département des Maladies des Voies Respiratoires, Hôpital Foch, Suresnes, France. 2. Department of Population Health, London School of Hygiene & Tropical Medicine, London, UK. 3. Emergency Department Clinical Research Unit, St George's Hospital, London, UK. 4. Emergency Department, The Royal London Hospital, London, UK. 5. Département de Biotechnologie de la Santé, Université Paris-Saclay, UVSQ, Inserm, Infection et inflammation, Montigny le Bretonneux, France. 6. Unité de Recherche Clinique, Inserm, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, Paris, France. 7. Department of Research and Clinical Innovation, Royal Centre for Defence Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, UK. 8. Department of Population Health, London School of Hygiene & Tropical Medicine, London, UK. Electronic address: Ian.Roberts@LSHTM.ac.uk.
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 mixed-effect 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-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 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-1) 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).
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 traumapatients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding traumapatients 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 mixed-effect 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-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 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-1) 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 traumapatients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).
Authors: Håkon Kvåle Bakke; Ole Martin Fuskevåg; Erik Waage Nielsen; Erik Sveberg Dietrichs Journal: Scand J Trauma Resusc Emerg Med Date: 2021-12-18 Impact factor: 2.953