Annelieke Kruithof successfully defends her PhD thesis

On 15 December 2021, Annelieke Kruithof successfully defended her PhD thesis titled ‘Evaluating the effects of sugammadex on coagulation in humans – reversed translational research to unravel off-target pharmacology’ at Leiden University!

Neuromuscular blocking agents (NMBAs) are used in general anesthesia to facilitate tracheal intubation and achieve skeletal muscle relaxation during surgery. The neuromuscular function can be restored by e.g. decreasing the concentration of the NMBA. This can be achieved by selective relaxant binding agents, of which sugammadex is the first-in-class. Sugammadex is a modified γ-cyclodextrin which encapsulates steroidal neuromuscular blocking agents rocuronium and vecuronium and thereby dose-dependently, rapidly and completely reverses their pharmacological effect in the post-operative setting.

An intravenous dose of 2 and 4 mg/kg sugammadex is recommended for routine reversal of moderate and deep blockade in adults, respectively, and 16 mg/kg sugammadex for reversal 3 minutes after an intubating dose of 1.2 mg/kg rocuronium. In vitro spiking experiments carried out during the development trajectory of sugammadex showed that 100 μg/mL sugammadex (corresponding with a dose of 8 mg/kg) significantly prolonged activated partial thromboplastin time (APTT) and international normalized ratio for prothrombin time PT(INR), but values remained within normal ranges. The effect of sugammadex on coagulation was not further evaluated in any clinical trial, rendering its clinical relevance unknown. 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. In an effort to address this concern, a post-hoc analysis of all adverse events related to hemorrhage in phase 2/3 trials was performed. This resulted in different regulatory decisions in July 2008. While marketing authorization was granted in the European Union, the FDA rejected the application because of deficiencies regarding the characterization of sugammadex effects on coagulation and allergic reactions. The EMA decided, as risk mitigation, to include the effect of sugammadex on APTT and PT(INR) in the summary of product characteristics (SPC). In addition, dedicated pharmacology studies to investigate the off-target effect of sugammadex on coagulation had to be undertaken as post-authorization commitment. Such studies were also required for resubmission to the FDA.

Annelieke's thesis describes a variety of in vitro, ex vivo and in vivo (clinical) pharmacology studies, performed by CHDR and collaborators, that provide more insight into the off-target effect of sugammadex on coagulation, with the aim to overcome the bleeding safety concerns raised by regulatory authorities. Read her thesis here

Annelieke was supervised by prof. dr. J. Burggraaf and dr. M. Moerland. The coagulation part was performed in collaboration with Good Biomarker Sciences (GBS), headed by prof. dr. C. Kluft, in Leiden.