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Thromb Haemost 2012; 108(05): 887-895
DOI: 10.1160/TH12-03-0184
Blood Coagulation, Fibrionolysis and Cellular Haemostasis
Schattauer GmbH

Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery

Shashank Rohatagi   *
1   Daiichi Sankyo India Pharma Private Ltd, Mumbai, India
,
Jeanne Mendell
2   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Helen Kastrissios
3   Pharsight Corporation, Mountain View, California, USA
,
Michelle Green
3   Pharsight Corporation, Mountain View, California, USA
,
Michelle Green
3   Pharsight Corporation, Mountain View, California, USA
,
Minggao Shi
2   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Indravadan Patel
2   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
,
Daniel E. Salazar
2   Daiichi Sankyo Pharma Development, Edison, New Jersey, USA
› Author Affiliations Financial support: This study was sponsored by Daiichi Sankyo.
Further Information

Publication History

Received: 22 March 2012

Accepted after major revision: 14 August 2012

Publication Date:
29 November 2017 (online)

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Summary

Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.

Keywords

Edoxaban - factor Xa inhibitor - population pharmacokinetics - venous thromboembolism

* Dr. Rohatagi is now with Piramal Life Sciences Ltd, Mumbai, India.


 

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