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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

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Abstract

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 NONMEM® 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 (≤60 kg), moderate renal impairment (CLCR ≤50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.

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Acknowledgments

This study was sponsored by Daiichi Sankyo Pharma Development. The authors would like to thank Dr. J. Nyberg for supporting this analysis and Quintiles Inc. for the generation of the NONMEM® dataset.

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Authors and Affiliations

  1. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Elke H. J. Krekels, Ronald Niebecker, Mats O. Karlsson, Kristin E. Karlsson, Ulrika S. H. Simonsson & Siv Jönsson

  2. Daiichi Sankyo Pharma Development, Edison, NJ, USA

    Raymond Miller

  3. Daiichi Sankyo, Co., Ltd., Tokyo, Japan

    Takako Shimizu

  4. Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Christian T. Ruff

  5. LACDR Division of Pharmacology, PO Box 9502, 2300 RA, Leiden, The Netherlands

    Elke H. J. Krekels

Authors
  1. Elke H. J. Krekels
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  2. Ronald Niebecker
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  3. Mats O. Karlsson
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  4. Raymond Miller
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  6. Kristin E. Karlsson
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  7. Christian T. Ruff
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  8. Ulrika S. H. Simonsson
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  9. Siv Jönsson
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Corresponding author

Correspondence to Elke H. J. Krekels.

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Conflict of interest

Mats Karlsson and Ulrika Simonsson have obtained consultancy fees from Daiichi Sankyo Pharma Development. Christian Ruff has served as a consultant and received honoraria from Daiichi Sankyo. Raymond Miller and Takako Shimizu are employees of Daiichi Sankyo. The other authors have no conflicts of interest to declare.

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Krekels, E.H.J., Niebecker, R., Karlsson, M.O. et al. Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial. Clin Pharmacokinet 55, 1079–1090 (2016). https://doi.org/10.1007/s40262-016-0378-3

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