Evaluating the effects of sugammadex on coagulation in humans: reversed translational research to unravel off-target pharmacology

Kruithof, A.C. (2021)

Doctoral Thesis

Sugammadex (Bridion®, laboratory code Org 25969) encapsulates neuromuscular blocking agents rocuronium and vecuronium and reverses their pharmacological effect in the post-operative setting. During the development trajectory of this first selective relaxant binding agent, it was found that sugammadex has an effect on standard coagulation laboratory coagulation assays. However, this off-target effect was not further evaluated in clinical studies. This raised safety concerns by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) during their review of the application for marketing authorization for sugammadex.
This thesis is comprised of a variety of in vitro, ex vivo and in vivo (clinical) pharmacology studies to provide more insight into the off-target effect of sugammadex on coagulation. The research involved the search for a mechanism, but also the clinical consequences on both primary and secondary hemostasis in clinical studies that included healthy volunteers. This evaluation was indispensable to overcome the bleeding safety concerns raised by both the EMA and the FDA.

• Org 25969
• Selective relaxant binding agent
• Factor Xa activity
• Ex vivo whole blood collagen-induced platelet aggregation methodology
• Sugammadex-aspirin interaction
• Sugammadex-enoxaparin interaction
• Sugammadex-unfractionated heparin interaction
• Anticoagulant
• Bleeding risk
• Question-based drug development

• All authors: Kruithof, A.C.
• Supervisor: Burggraaf, J.; Kluft, C.
• Co-supervisor: Moerland, M.
• Committee: Eikenboom, H.C.J.; Cannegieter, S.C.; Dahan, A.; Cate, H. ten; Middeldorp, S.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2021-12-15