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Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers

Kane, Z; Picetti, R; Wilby, A; Standing, JF; Grassin-Delyle, S; Roberts, I; Shakur-Still, H; (2021) Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers. European Journal of Pharmaceutical Sciences , 164 , Article 105893. 10.1016/j.ejps.2021.105893. Green open access

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Abstract

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependent on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. METHODS: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n=48 participants). The model was verified using separate IV and oral validation datasets (n=26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. RESULTS: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67 % and Tmax from 2.6 to 3.2 and 0.4 to 1.0 hours following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. CONCLUSIONS: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 minutes and be maintained above this level for approximately 3 hours, achieving systemic exposure (AUC0-6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.

Type: Article
Title: Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejps.2021.105893
Publisher version: https://doi.org/10.1016/j.ejps.2021.105893
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Pharmacokinetics, intramuscular, intravenous, oral, physiologically based pharmacokinetic modelling, tranexamic acid
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10129752
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