Anticoagulation With Argatroban for Elective Percutaneous Coronary Intervention: Population Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationship of Coagulation Parameters

Abstract

The synthetic direct thrombin inhibitor argatroban has a rapid onset and offset of anticoagulation. However, there are no data about the pharmacokinetic-pharmacodynamic (PK-PD) relationship of argatroban in patients undergoing contemporary percutaneous coronary intervention (PCI) and no data about other coagulation parameters than activated clotting time (ACT) in this setting. In the ARG-E04-trial, 140 patients were randomly assigned to argatroban (250, 300, or 350 µg/kg as bolus before PCI, followed by 15, 20, or 25 µg/kg/min infusion) or unfractionated heparin (70-100 IU/kg bolus). A 2-compartment model with first-order elimination adequately described the pharmacokinetic profile of argatroban over all 3 dosing groups. Clearance (CL) and distribution volumes (V1 and V2) were 21 L/h, 9.2 L, and 6.6 L, respectively. A significant sigmoidal E(max) relationship was established between the argatroban plasma concentration and the response in ACT and the endogenous thrombin potential (ETP), whereas the response in activated partial thromoplastin time (aPTT), ecarin time (ECA-T), and prothrombinase-induced clotting time (PiCT) could be described by a nonsigmoidal E(max) model. This study proves a relatively small interindividual variability of both PK and PK-PD properties of argatroban even at high doses and supports the profile of argatroban as a drug with a predictive dose-effect relationship and therefore good controllability.

Monitoring and Reversal of Anticoagulation and Antiplatelets

“…There seems to be a consistent dose-effect relationship using argatroban, regardless of the assay used. A study evaluating the pharmacokinetic-pharmacodynamic relationship of argatroban 92 showed that in contrast to UFH, argatroban causes a faster response in all coagulation parameters (a quicker increase after initiation and normalization after stopping medication). This study also concluded that ACT is the most appropriate method for monitoring the effect of argatroban in patients undergoing PCI.…”

Les inhibiteurs directs de la thrombine, l’hirudine, la bivalirudine, l’argatroban, et le dabigatran etexilate

“…Dans les TIH, l'utilisation grandissante de l'argatroban a permis de mieux définir la posologie à l'initiation du traitement 0,5 à 1 g/kg par minute, puis son ajustement dans les deux heures suivantes à l'aide de la mesure du TCA et/ou du dosage de l'argatroban (Hemoclot-Hyphen Biomed) [45]. Le TCA ne doit pas dépasser 100 secondes.…”

“…Le retentissement de l'argatroban sur les tests de coagulation et ses caractéristiques pharmacocinétiques ont été très attentivement analysés dans une étude récente chez des patients ayant une PCI [45].…”

“…La coadministration avec l'argatroban de la warfarine n'affecte pas les propriétés pharmacocinétiques de celle-ci mais l'argatroban augmente la valeur de l'INR au moment du relais [46]. L'interférence de l'argatroban sur le temps de Quick à partir duquel est calculé l'INR est importante, entraînant une conduite particulière du relais argagtroban-AVK une fois que la thrombopénie a été corrigée sur deux jours consécutifs [45].…”

Development of a fast and simple liquid chromatography–tandem mass spectrometry method for the quantitation of argatroban in patient plasma samples

“…Herein, we describe a method for direct quantitation of argatroban in plasma samples using a rapid ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay with a greater analytical measurement range than previously reported LC-MS/MS methods [6,7,11]. The UPLC-MS/MS method is compared to a commercially available, Hemoclot Thrombin Inhibitors [HTI] (HYPHEN BioMed) indirect activity-based clotting assay for argatroban measurement and recommendations are made with regards to clinical utility and advantages of each method.…”