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Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. LACDR Div Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Daiichi Sankyo Pharma Dev, Edison, NJ USA..
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2016 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 55, no 9, 1079-1090 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations.

Methods: Model development was performed using NONMEMA (R) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CLCR), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance.

Results: A two-compartment model with first-order elimination and first-order absorption after an absorption lag-time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CLCR. Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance.

Conclusion: Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (aecurrency sign60 kg), moderate renal impairment (CLCR aecurrency sign50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.

Place, publisher, year, edition, pages
2016. Vol. 55, no 9, 1079-1090 p.
National Category
Pharmaceutical Sciences
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URN: urn:nbn:se:uu:diva-305543DOI: 10.1007/s40262-016-0378-3ISI: 000382154200005PubMedID: 26951208OAI: oai:DiVA.org:uu-305543DiVA: diva2:1038980
Available from: 2016-10-20 Created: 2016-10-19 Last updated: 2016-10-20Bibliographically approved

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Karlsson, Mats O.Simonsson, Ulrika S. H.Jönsson, Siv
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