Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects

Abstract

Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects. J Thromb Haemost 2016; 14: 316-23. Essentials• It is unknown whether single rivaroxaban doses should best be administered in the morning or evening.• Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban.• Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations.• Evening intake of rivaroxaban better matches the morning hypofibrinolysis.Summary. Background: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. Materials and methods: Sixteen healthy male or female volunteers with a mean age of 26 AE 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an antiactivated factor X assay and liquid chromatography-mass spectrometry. Main results: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL À1 [95% con- 106 AE 34 nmol L À1 , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. Conclusions: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.

The Effect of Acute Training and Circadian Rhythm on Blood Hemostasis in Female Athletes

“…According to the findings, exercises in the morning have a greater effect on the blood coagulation time. 20,33 Ethical Approval In this study ethical considerations including informed consent in writing of the subjects was observed. Also the exercise protocol was performed in the presence of a medical assistant in the event of an accident or potential injury.…”

Adropin as a potential mediator of the metabolic system‐autonomic nervous system‐chronobiology axis: Implementing a personalized signature‐based platform for chronotherapy

“…133 Concentrations of rivaroxaban were higher 12 h after evening administration than 12 h after morning administration. 134 Following administration of potentially lethal and sublethal doses of isoniazid to mice, a decrease in cytopenia and increased survival was found to be related to the time of drug treatment. 135 These data suggest that the timing of the administration of a drug determines the overall effect of the drugs.…”

“…Among patients taking clopidogrel after STEMI, platelet inhibition was reduced when the drug was administered during midmorning hours 133 . Concentrations of rivaroxaban were higher 12 h after evening administration than 12 h after morning administration 134 . Following administration of potentially lethal and sublethal doses of isoniazid to mice, a decrease in cytopenia and increased survival was found to be related to the time of drug treatment 135 …”

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“…For reduction in risk of stroke in nonvalvular atrial fibrillation, rivaroxaban is taken once daily with the evening meal; for other indications, the 15 mg and 20 mg once daily formulation should be taken with food, while the 10 mg once daily tablet can be taken with or without food. Brunner-Ziegler, et al observed higher rivaroxaban concentrations 12 h after drug administration of 10 mg rivaroxaban (53.3 ng/mL versus 23.3 ng/mL; P < 0.01) and longer lasting suppression effect (24 h instead of 12 h relative to the "no drug" baseline values) following evening administration of 10 mg rivaroxaban in sixteen healthy volunteers compare to morning intake [45]. This pharmacokinetic and pharmacodynamic changes could better match the morning hypofibrinolysis and might further improve the efficacy and safety of rivaroxaban treatment.…”