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Br J Clin Pharmacol ; 88(6): 2982-2987, 2022 06.
Article in English | MEDLINE | ID: covidwho-1583678


Critically ill COVID-19 patients are at high risk of thromboembolic events despite routine-dosed low-molecular-weight heparin thromboprophylaxis. However, in recent randomized trials increased-intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti-Xa activities on frequent timepoints in 15 critically ill COVID-19 patients receiving dalteparin and performed PK analysis by nonlinear mixed-effect modelling. A linear one-compartment model with first-order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased-intensity dalteparin to result in anti-Xa activities well over prophylactic targets (0.2-0.4 IU/mL) in the majority of patients. Therapeutic-intensity dalteparin results in supratherapeutic anti-Xa levels (target 0.6-1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti-Xa measurements should guide high-intensity dalteparin in critically ill COVID-19 patients.

COVID-19 , Venous Thromboembolism , Anticoagulants , COVID-19/drug therapy , Critical Illness/therapy , Dalteparin/adverse effects , Factor Xa Inhibitors/pharmacokinetics , Heparin, Low-Molecular-Weight , Humans , Venous Thromboembolism/chemically induced , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & control
Am J Cardiovasc Drugs ; 20(6): 525-533, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-755898


Human factor Xa (FXa) is a serine protease of the common coagulation pathway. FXa is known to activate prothrombin to thrombin, which eventually leads to the formation of cross-linked blood clots. While this process is important in maintaining hemostasis, excessive thrombin generation results in a host of thrombotic conditions. FXa has also been linked to inflammation via protease-activated receptors. Together, coagulopathy and inflammation have been implicated in the pathogenesis of viral infections, including the current coronavirus pandemic. Direct FXa inhibitors have been shown to possess anti-inflammatory and antiviral effects, in addition to their established anticoagulant activity. This review summarizes the pharmacological activities of direct FXa inhibitors, their pharmacokinetics, potential drug-drug interactions and adverse effects, and the details of clinical trials involving direct FXa inhibitors in coronavirus disease 2019 (COVID-19) patients.

COVID-19/drug therapy , COVID-19/physiopathology , Factor Xa Inhibitors/pharmacology , Factor Xa Inhibitors/therapeutic use , Blood Coagulation/drug effects , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/physiopathology , Cytokines/biosynthesis , Drug Interactions , Factor Xa/metabolism , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/pharmacokinetics , Half-Life , Humans , Inflammation Mediators/metabolism , Metabolic Clearance Rate , Multiple Organ Failure/physiopathology , Multiple Organ Failure/prevention & control , Pandemics , Protein Binding/physiology , SARS-CoV-2 , Severity of Illness Index