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

Stanislas Grassin-Delyle,Iléana Runge,Haleema Shakur-Still,Michaela Semeraro,Monica Arribas,Jean-Marc Treluyer,Ian Roberts,Raoul Mansukhani,Elodie Lamy

doi:10.3389/fphar.2021.764379

Abstract

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition.

Highlights

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
To assess whether capillary samples can be used to estimate plasma tranexamic acid (TXA) concentrations, we examined the association between plasma TXA levels and those estimated from volumetric absorptive micro-sampling (VAMS) capillary blood samples using Equation 1 below, as described in our previous paper (Grassin-Delyle et al, 2021a): Cplasma
Whole blood tranexamic concentrations in samples collected using the VAMS devices correspond closely to those measured in liquid blood samples collected by venepuncture

Summary

Introduction

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). 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). We initiated a programme of pharmacokinetic (PK) research on alternative routes of TXA administration. Finding new routes of TXA administration is of particular interest in low- and middle-income countries and several studies have been initiated in these settings. We report the accuracy of TXA concentrations in blood collected using theses VAMS devices

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Results

Conclusion