Edoxaban Dosing Time Affects Blood Coagulation Inhibition in Rats

Area of Science:

• Pharmacology
• Chronobiology
• Hemostasis

Background:

• Coagulation and fibrinolysis exhibit daily rhythms, influencing anticoagulant effectiveness.
• The optimal dosing time for once-daily edoxaban, a Factor Xa inhibitor, remains undetermined.

Purpose of the Study:

• To investigate the impact of dosing time on edoxaban's efficacy in inhibiting coagulation and thrombus formation.
• To evaluate the relationship between edoxaban's pharmacokinetic profile and its antithrombotic activity in rats.

Main Methods:

• Wistar rats received edoxaban (10 mg/kg) or vehicle at the start of the light (ZT2) or dark (ZT14) phase.
• Coagulation factor activity and drug concentrations were measured at various time points.
• Thrombus formation was assessed after inferior vena cava ligation at ZT4 or ZT16.

Main Results:

• Coagulation Factor X activity was higher during the light phase.
• Edoxaban administered at ZT2 (light phase) showed more potent inhibition of Factor X activity and thrombus formation than at ZT14 (dark phase).
• Higher blood concentrations of edoxaban after ZT2 dosing contributed to enhanced inhibition.

Conclusions:

• Morning administration (ZT2) of edoxaban resulted in greater inhibition of coagulation and thrombus formation compared to evening administration (ZT14).
• The enhanced efficacy during the light phase is partly due to achieving higher drug concentrations when coagulation activity is naturally elevated.
• Optimizing edoxaban dosing time to align with daily hypercoagulability may enhance its therapeutic effectiveness.