Sugammadex: A selective relaxant binding agent for neuromuscular block reversal

Sugammadex is a novel, first-in-class, selective relaxant binding agent that encapsulates the nondepolarizing aminosteroid muscle relaxants rocuronium and vecuronium, reversing and preventing their neuromuscular block (NMB) action. Clinical trials have demonstrated that sugammadex is effective in reversing both rocuronium- and vecuronium-induced NMB, and the agent has been well tolerated in studies.

Key Points

Abstract

Neuromuscular block (NMB) drugs are used to facilitate endotracheal intubation for mechanical ventilation and to provide muscle relaxation in the operating room and intensive care unit. To decrease the risk for postoperative residual paralysis, NMB is reversed at the end of surgery. Sugammadex is a novel, first-in-class, selective relaxant binding agent that encapsulates the nondepolarizing aminosteroid muscle relaxants rocuronium and vecuronium, reversing and preventing their NMB action. Sugammadex is unique compared with other NMB reversal drugs in that it can reverse a light, moderate, or deep NMB, thus eliminating the need for acetylcholinesterase inhibitors such as neostigmine and cholinergic antagonists such as glycopyrrolate or atropine. Clinical trials have demonstrated that sugammadex is effective in reversing both rocuronium- and vecuronium-induced NMB, and the agent has been well tolerated in studies. An NDA for sugammadex was submitted in October 2007. In August 2008, the manufacturer announced that FDA had issued a nonapprovable letter for sugammadex, but the manufacturer is continuing phase 3 trials for this agent. (Formulary. 2009;44:13–21.)

Rocuronium, vecuronium, and pancuronium are aminosteroid nondepolarizing neuromuscular block (NMB) drugs that are frequently used during surgery to provide optimal conditions for muscle paralysis for endotracheal intubation, surgical exposure, and patient immobility. In current practice with existing drugs, NMB reversal is imperfect and occasionally ineffective because 1) NMB reversal is an indirect effect because of the increased acetylcholine concentration needed for reversal; 2) rapid reversal of a deep, profound, complete block is not possible; 3) side effects such as autonomic parasympathetic nervous system responses (bradycardia) may occur.1,2

If the acetylcholine concentration is not high enough, muscle relaxant competition will not be effective, and incomplete reversal may occur, resulting in residual paralysis. Inadequate reversal occurs when the muscle relaxant concentration is close to the acetylcholine concentration necessary for normal muscle function.3–5 Residual paralysis exhibited as muscle weakness in the postanesthesia care unit (PACU) or intensive care unit (ICU) may initially be difficult to detect, as the commonly used clinical tests and monitors are relatively insensitive to detect a residual block.1,2,5–7

Limitations of the present anticholinesterase agents, such as neostigmine, include their ineffectiveness to reverse a profound deep NMB and side effects that require a comedication such as glycopyrrolate.3 Avoiding a profound block helps to prevent prolonged recovery times and minimizes the side effect of residual paralysis.1,3,4

Anticholinesterase medications have been used to reverse NMB for many years, with neostigmine currently the most common reversal agent. The anticholinesterase drugs have similar pharmacokinetic parameters despite different mechanisms of action. Neostigmine and pyridostigmine have a relatively long onset of action (7–11 and 10–16 min, respectively), whereas edrophonium has an onset of 1 to 2 minutes.3

Past research has concentrated on the anticholinesterase inhibitors. Present research has concentrated on novel agents that effectively reverse NMB without side effects. An ideal NMB reversal agent would: 1) have rapid onset; 2) be fully effective and predictable; 3) reverse any degree of block; and 4) be effective in the presence of all intravenous (IV) and inhalation anesthetics, with minimal or no side effects.

Sugammadex (Schering-Plough) is a novel, first-in-class, selective relaxant binding agent that encapsulates the nondepolarizing aminosteroid muscle relaxants rocuronium and vecuronium, reversing and preventing their NMB action. In October 2007, the manufacturer submitted an NDA for sugammadex for the routine reversal of shallow and profound rocuronium- or vecuronium- induced NMB and for immediate reversal of rocuronium-induced NMB at 3 minutes after administration of rocuronium. Priority review was granted in December 2007. In March 2008, FDA's Anesthetics and Life Support Advisory Committee unanimously recommended approval of sugammadex. In August 2008, the manufacturer announced that FDA had issued a nonapprovable letter for the agent. Schering-Plough has stated that it remains committed to bringing this agent to market; the company is currently conducting additional phase 3 studies.

CHEMISTRY AND PHARMACOLOGY

Cyclodextrins are cyclic oligosaccharide carbohydrates formed from the degradation of starch, with a hydrophobic inner core and hydrophilic outer area. Properties of cyclodextrins include water solubility, nonmetabolism, and renal excretion as a function of the glomerular filtration rate (GFR). The inner lipophilic core causes chemical encapsulation of hydrophobic molecules, allowing for stabilization and solubilization. The alpha, beta, and gamma cyclodextrins have 6, 7, and 8 glucose units, respectively. The number of glucose units determines the internal diameter and volume of the inner core cavity and thus the size of molecule that can be encapsulated.8–10

Recovery from NMB occurs through an increase in plasma acetylcholine concentration or a decrease in the concentration of NMB agent at the neuromuscular junction due to metabolism and excretion. Chemical encapsulation has been proposed as a method to terminate the action of NMB with minimal adverse effects. This hypothesis has led to the investigation of cyclodextrins as selective reversal binding agents of NMB. Sugammadex's mechanism of action is via the novel concept of direct NMB inactivation in the plasma, which occurs through a very rapid chemical encapsulation selective binding interaction between the NMB drug and the cyclodextrin molecule.8–10

Sugammadex, a modified gamma cyclodextrin, is the first in a new class of agents called selective relaxant binding agents, which bind and terminate the aminosteroid nondepolarizing muscle relaxants. The gamma cyclodextrins were determined to have the best size to encapsulate the aminosteroid muscle relaxants.10–12

X-ray crystallography has demonstrated sugammadex's encapsulation and strong binding properties with rocuronium.13 Sugammadex binds rocuronium 1:1 and thereby decreases the active plasma concentration of rocuronium to zero. Sugammadex is specific for the aminosteroidal nondepolarizing muscle relaxants, with rocuronium having the strongest binding affinity, followed by vecuronium and then pancuronium. Sugammadex has 2.5 times the affinity and selectivity for rocuronium as it has for vecuronium. Sugammadex has no affinity for succinylcholine, cisatracurium, atracurium, or mivacurium.10,11