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 dependant 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 h 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 min and be maintained above this level for approximately 3 h, 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.
Highlights
Acute severe bleeding is a leading cause of death (Wang et al, 2015)
All publications were in English, except for one in Japanese (SANO et al, 1976) that was translated with the help of a Japanese native speaker
Visych et al (2016) reports a Caco-2 average permeation rate of 12.4 × 10–06 ± 0.1 cm/s, (Visych et al, 2016) no marker data is published alongside thereby making the result of limited use in physiologically based pharmacokinetic modelling (PBPK) model development
Summary
Acute severe bleeding is a leading cause of death (Wang et al, 2015). Traumatic intracranial bleeding are common causes of death and disability with an estimated 69 million new cases each year (Dewan et al, 2018). We employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). 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. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended
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