Abstract
BackgroundTight monitoring of efficacy and safety of anticoagulants such as warfarin is imperative to optimize the benefit-risk ratio of anticoagulants in patients. The standard tests used are measurements of prothrombin time (PT), usually expressed as international normalized ratio (INR), and activated partial thromboplastin time (aPTT).ObjectiveTo leverage a previously developed quantitative systems pharmacology (QSP) model of the human coagulation network to predict INR and aPTT for warfarin and rivaroxaban, respectively.MethodsA modeling and simulation approach was used to predict INR and aPTT measurements of patients receiving steady-state anticoagulation therapy. A previously developed QSP model was leveraged for the present analysis. The effect of genetic polymorphisms known to influence dose response of warfarin (CYP2C9, VKORC1) were implemented into the model by modifying warfarin clearance (CYP2C9 *1: 0.2 L/h; *2: 0.14 L/h, *3: 0.04 L/h) and the concentration of available vitamin K (VKORC1 GA: −22% from normal vitamin K concentration; AA: −44% from normal vitamin K concentration). Virtual patient populations were used to assess the ability of the model to accurately predict routine INR and aPTT measurements from patients under long-term anticoagulant therapy.ResultsThe introduced model accurately described the observed INR of patients receiving long-term warfarin treatment. The model was able to demonstrate the influence of genetic polymorphisms of CYP2C9 and VKORC1 on the INR measurements. Additionally, the model was successfully used to predict aPTT measurements for patients receiving long-term rivaroxaban therapy.ConclusionThe QSP model accurately predicted INR and aPTT measurements observed during routine therapeutic drug monitoring. This is an exemplar of how a QSP model can be adapted and used as a model-based precision dosing tool during clinical practice and drug development to predict efficacy and safety of anticoagulants to ultimately help optimize anti-thrombotic therapy.
Highlights
Venous thromboembolism (VTE) is a common cardiovascular disease, associated with a high morbidity and mortality rate (Naess et al, 2007; Beckman et al, 2010)
The model was able to demonstrate the influence of genetic polymorphisms of Cytochrome P4502C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on the international normalized ratio (INR) measurements
The quantitative systems pharmacology (QSP) model accurately predicted INR and activated partial thromboplastin time (aPTT) measurements observed during routine therapeutic drug monitoring
Summary
Venous thromboembolism (VTE) is a common cardiovascular disease, associated with a high morbidity and mortality rate (Naess et al, 2007; Beckman et al, 2010). The gold standard of care for VTE is warfarin, making it the most commonly prescribed anticoagulant currently on the market (Garcia and Spyropoulos, 2008). Warfarin acts via the inhibition of the vitamin K epoxide reductase (VKOR) within the vitamin K (VK) cycle. It effectively inhibits the production of all VKdependent coagulation factors, namely factors II, VII, IX, X, protein C (PC), and protein S (PS) (Thompson, 1977; Weiss et al, 1987; Zivelin et al, 1993). Several alternatives to warfarin have entered the market over the past years. Tight monitoring of efficacy and safety of anticoagulants such as warfarin is imperative to optimize the benefit-risk ratio of anticoagulants in patients. The standard tests used are measurements of prothrombin time (PT), usually expressed as international normalized ratio (INR), and activated partial thromboplastin time (aPTT)
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