Population pharmacokinetic‐pharmacodynamic modeling analysis of intrinsic FXa and bleeding from edoxaban treatment
- 2 May 2014
- journal article
- research article
- Published by Wiley in The Journal of Clinical Pharmacology
- Vol. 54 (8), 910-916
- https://doi.org/10.1002/jcph.306
Abstract
Edoxaban is an oral, once‐daily, direct factor Xa (FXa) inhibitor that has been evaluated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of venous thromboembolism (VTE) recurrence. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and logistic regression analyses were used to explore the clinical data from phase 1 and 2 studies to determine the relationship among PK exposure, PD response, and bleeding risk. Population PK/PD modeling was performed using plasma edoxaban concentration data from combined phase 1 and 2 studies and using intrinsic FXa data from a phase 2 AF study. A 2‐compartment PK model adequately described the combined PK data, and a dynamic binding model characterized the dynamics of the intrinsic factor X activity (iFXa) data. Logistic regression analysis then identified the relationship between the iFXa and the observed bleeding risk. The more protracted suppression of FXa over the dosing interval for a 30‐mg twice‐daily dose compared with a 60‐mg once‐daily dose offers an explanation for the significantly higher bleeding rate at the former dose.Keywords
This publication has 14 references indexed in Scilit:
- Edoxaban versus Warfarin in Patients with Atrial FibrillationNew England Journal of Medicine, 2013
- Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillationThrombosis and Haemostasis, 2012
- RivaroxabanClinical Pharmacokinetics, 2011
- Apixaban versus Warfarin in Patients with Atrial FibrillationNew England Journal of Medicine, 2011
- Rivaroxaban versus Warfarin in Nonvalvular Atrial FibrillationNew England Journal of Medicine, 2011
- Pharmacokinetics, Pharmacodynamics, and Monte Carlo SimulationThe Pediatric Infectious Disease Journal, 2010
- Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillationThrombosis and Haemostasis, 2010
- DU‐176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profilesJournal of Thrombosis and Haemostasis, 2008
- A Model for the Stoichiometric Regulation of Blood CoagulationJournal of Biological Chemistry, 2002
- Prediction of Creatinine Clearance from Serum CreatinineNephron, 1976