Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation

Autor: Robert P. Giugliano, Helen Kastrissios, Tomas S. Bocanegra, Simon Zhou, Michelle Green, Shashank Rohatagi, Indravadan Patel, Timothy J. Carrothers, Bruce E Dornseif, SaeHeum Song, Satoshi Kunitada, Minggao Shi, Jeanne Mendell, Daniel E. Salazar, Elliott M. Antman, Masaya Tachibana
Rok vydání: 2012
Předmět:
Male
medicine.medical_specialty
medicine.drug_mechanism_of_action
Pyridines
Factor Xa Inhibitor
Administration
Oral
Hemorrhage
030204 cardiovascular system & hematology
Models
Biological
Risk Assessment
030226 pharmacology & pharmacy
03 medical and health sciences
chemistry.chemical_compound
Cmin
0302 clinical medicine
Pharmacokinetics
Risk Factors
Edoxaban
Internal medicine
Atrial Fibrillation
Humans
Medicine
Computer Simulation
Drug Interactions
ATP Binding Cassette Transporter
Subfamily B
Member 1
Blood Coagulation
Stroke
Models
Statistical
Dose-Response Relationship
Drug
business.industry
Anticoagulants
Atrial fibrillation
Hematology
medicine.disease
Clinical trial
Thiazoles
Logistic Models
Treatment Outcome
Clinical Trials
Phase III as Topic
chemistry
Research Design
Anesthesia
Concomitant
Factor Xa
Female
Kidney Diseases
business
Factor Xa Inhibitors
Zdroj: Thrombosis and Haemostasis. 107:925-934
ISSN: 2567-689X
0340-6245
Popis: SummaryEdoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.The results of this study were previously presented at the 2009 International Society on Thrombosis and Haemostasis, July 2009, Boston, Massachusetts, USA.
Databáze: OpenAIRE
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