Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects

ABSTRACT

Objective: The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of rivaroxaban – a novel, oral, direct Factor Xa (FXa) inhibitor – in healthy elderly subjects.

Research design and methods: In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 48 subjects (aged 60–76 years) were randomized to receive a single oral dose of 30, 40 or 50 mg of rivaroxaban or placebo.

Results: Rivaroxaban was absorbed rapidly, reaching peak plasma concentration (C_max) 4 h after dosing in all groups. Bioavailability, in terms of the area under the plasma concentration–time curve (AUC) and C_max, increased slightly (less than dose proportionally) after administration of rivaroxaban 40 mg compared with 30 mg, but was not increased further with rivaroxaban 50 mg. Rivaroxaban pharmacodynamic effects (inhibition of FXa activity and prolongation of prothrombin time, activated partial thromboplastin time and HepTest) all showed a similar pattern, with maximum inhibition of FXa activity increasing from 68% after rivaroxaban 30 mg to 75% after 40 mg and no further increase with the 50 mg dose. Most adverse events were mild; observed rates were less than placebo for the 30 and 40 mg dose groups, and similar to placebo for 50 mg. No differences were found between male and female subjects. Effects of rivaroxaban doses above 50 mg were not investigated in this study.

Conclusions: Each single dose of rivaroxaban was well tolerated, with predictable pharmacokinetics and pharmacodynamics at doses up to 40 mg, and provided effective anticoagulation in healthy elderly subjects. Adverse events were somewhat elevated in the 50 mg group, but given the small sample size, no specific conclusions can be drawn about this dosing level.

Key words: :

• Elderly
• Factor Xa inhibitor
• Oral anticoagulant
• Rivaroxaban
• Thromboembolic disorders

Acknowledgements

This study was supported by Bayer HealthCare AG. All authors are employees of Bayer HealthCare AG. The authors wish to acknowledge Toby Allinson and Chris Thomas of Chameleon Communications, who provided medical writing assistance with funding from Bayer HealthCare.