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Pharmacokinetic and Pharmacodynamic Analyses of Nafamostat in ECMO Patients: A Comparative Study of Central Vein and ECMO Machine Samples

Research Square (Research Square)(2023)

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Abstract
Abstract Background This study addresses the knowledge gap concerning the optimal dosage adjustment of nafamostat mesylate in extracorporeal membrane oxygenation (ECMO) by investigating its pharmacokinetics/pharmacodynamics properties. Specifically, we examine the exposure-response relationship between nafamostat concentration and activated partial thromboplastin time (aPTT) in ECMO patients. Methods Prospectively, 24 patients were enrolled in this study. Nafamostat infusion was administered continuously through a dedicated stopcock in the drainage pathway before the ECMO pump, starting at 15 mg/h. The maintenance dose of nafamostat was adjusted to maintain the target aPTT range of 40 to 80 seconds. Blood samples were collected from both the patient's central venous catheter and the ECMO circuit. Pharmacokinetics/pharmacodynamics analyses were performed using a nonlinear mixed effects model. Results The time-varying nafamostat concentrations measured from patient catheter and ECMO circuit were best described by a two-compartment model. In the patient model, the clearance was 189 L/h, and the steady-state volume of distribution was 62.01 L. In the ECMO model, the clearance was 85.2 L/h, and the steady-state volume of distribution was 40.63 L. The mechanism by which the anticoagulant effect of nafamostat increased aPTT in both models was well explained by a turnover model in which increasing concentration of nafamostat inhibited the decrease in aPTT. In the patient model, nafamostat was found to decrease the rate constant for aPTT reduction by up to 35.5%, with an IC50 of 350 µg/L. In the ECMO model, nafamostat was observed to decrease the rate constant for aPTT reduction by up to 43.6%, with an IC50 of 581 µg/L. Conclusions When developing the pharmacokinetics/pharmacodynamics model of nafamostat using patient and ECMO samples, we employed two-compartment and turnover models for pharmacokinetics and pharmacodynamics, respectively. Notably, there were substantial differences in the estimated parameter values. Considering the substantial interindividual variability observed in the pharmacokinetics/pharmacodynamics of nafamostat, the development of a highly predictive model that incorporates relevant covariates and considers the sampling site holds great promise in achieving desired anticoagulant effects, particularly in ECMO-treated patients who are at a heightened risk of bleeding.
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Key words
nafamostat,ecmo patients,pharmacodynamic analyses,central vein
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