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Published on 29 April 2009

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Sugammadex for the reversal of neuromuscular blockade

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Sugammadex is a new pharmacological agent that reverses the effects of the steroidal nondepolarising neuromuscular blocking agents, primarily rocuronium, by a novel mechanism

Emma Graham-Clarke
BPharm MPhil, MRPharmS

Consultant Pharmacist
Critical Care, AHP/HCS
Lead BBCCCN

Department of Anaesthetics
City Hospital
Birmingham
UK

Sugammadex is described as a modified gamma (γ) cyclodextrin. The cyclodextrins are a group of cyclic oligosaccharide carbohydrates derived from starch. The ring portion of the cyclodextrins can contain a varying number of glucose units; γ indicates that the ring in sugammadex comprises eight glucose molecules. Each of these glucose units in sugammadex has a modified “tail”, which helps to extend the central core. The outer surface of the molecule is hydrophilic whilst the central core or cavity is hydrophobic.[1] In appearance a 3D model would appear as a cone-shaped doughnut with a hollow core.

Mechanism of action
This novel cone structure allows the drug to “engulf” and complex the steroidal neuromuscular blocking agent (NMBA) and hence inactivate it. The activity of sugammadex is primarily against rocuronium, with some activity against vecuronium and much less activity against pancuronium. Each molecule of sugammadex will engulf a single molecule of rocuronium.

The current method to reverse NMBAs is to administer an anticholinesterase agent such as neostigmine, which prevents the breakdown of acetylcholine, but this needs to be given with another drug such as atropine or glycopyrronium to lessen its side-effects.[2] By engulfing the NMBA and rendering it inactive, sugammadex acts in a completely different way.

Sugammadex has a very tight affinity for binding the NMBA and a low rate of dissociation.[1] As a result, active NMBA is removed from plasma, creating a concentration gradient that moves more NMBA away from the neuromuscular junction into plasma where it too can be inactivated. This action allows neurotransmission to recommence, restoring muscle tone. Because of the strong affinity that sugammadex has for NMBAs, there is minimal risk that free NMBAs will be released from the complex before excretion and hence residual muscle weakness is not seen.

Pharmacokinetics[3]
The sugammadex molecule is highly hydrophilic and this is reflected in its volume of distribution, which is in the range of 11—14 litres, indicating distribution throughout body water. Neither it nor the bound complex appears to be protein-bound. Elimination is primarily through renal excretion (more than 95%) and no metabolites of sugammadex have been seen. The elimination half-life in adults with normal renal function is 1.8 hours (with a plasma clearance of 88 ml/min). As expected, the half-life increases as renal function decreases, reaching a half-life of 5.2 hours in moderate renal impairment. Prolongation of the half-life is also seen in elderly patients, who tend to have slightly poorer renal function.

In paediatric patients the reverse is true: the elimination half-life reduces to 1.7 hours for adolescent patients, and 0.9 hours for children. The volume of distribution increases with age in children, reflecting a change in body water distribution, and the clearance also increases. Data for infants, newborn children and neonates are limited, and currently sugammadex is not recommended in these age groups.

Dose
In theory, for complete reversal of the neuromuscular block, dosing of sugammadex needs to be based on a molar-to-molar basis with the NMBA. In practice, reversal of the block is not initiated until some recovery is seen in neuromuscular function, indicating that the residual amount of NMBA in the body is less than the original dose administered. Hence the dose of sugammadex that needs to be given to reverse the effects is less than may have been calculated from first principles, and varies depending on the degree of spontaneous recovery from the block.

A dose-finding study by Shields et al, published in 2006, studied reversal of rocuronium-induced prolonged neuromuscular blockade in 30 adult patients.[4] The doses of sugammadex used were 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg and 6 mg/kg, and the dose of rocuronium used was 0.6 mg/kg for initiation of block and subsequent amounts as needed during the operation. Train of four (TOF) monitoring was used to assess the level of the block and sugammadex was given when the block level reached T2. (In train of four monitoring two electrodes are applied to the skin over a nerve, usually the ulnar nerve. A small current is passed sufficient to generate a twitch in the muscle. To monitor depth of neuromuscular blockade a series of four such stimuli are applied at 0.5 second intervals and the resultant number of twitches is counted. T0 is the absence of twitches, T2 is the presence of two twitches in the two second time period, whilst T4 is equivalent to full muscle activity.)

The  mean time to reach a T4/T1 ratio of 0.9 was similar in the 2 mg/kg and 4 mg/kg dosing groups (1.44 and 1.22 minutes, respectively), and somewhat longer in the 0.5 mg/kg and 1 mg/kg groups (6.49 and 2.23 minutes, respectively). The mean time for the 6 mg/kg group was 2.37 minutes; however, the range was 1.08-3.56 minutes. For all doses of 1 mg/kg or above, complete reversal was achieved in four minutes without any reappearance of the block. They concluded that the three doses, 2 mg/kg, 4 mg/kg and 6 mg/kg, lay on the plateau of the dose-response curve.

A similar study by Groudine et al compared the effects of sugammadex against two different doses of rocuronium, 0.6 mg/kg and 1.2 mg/kg, using five different doses of sugammadex (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg).5 Because of protocol exclusions some of the sample groups were small (one or two patients); however, the findings were similar to the Shield study in that a dose of 2 mg/kg or 4 mg/kg produced appropriate reversal, with little benefit from a larger dose, and extended recovery from the smaller doses. Three adverse events thought by the investigators to be linked to the use of sugammadex could in fact be attributed to either incomplete reversal, or unexpected rapid reversal (coughing on the endotracheal tube).

De Boer et al studied Rhesus monkeys to assess whether a second dose of rocuronium given subsequent to a dose of sugammadex was effective.[6] They found that even after two half-lives of sugammadex had elapsed between the administration of the drug and the administration of NMBA the effects of sugammadex were still apparent. The summary of product characteristics (SMPC) states that if further  neuromuscular blockade is needed within 24 hours of administration of sugammadex then an alternative class of NMBA should be used.[3]

Comparison with standard reversal agents
An open-label study was conducted by Sacan et al to compare sugammadex with the traditional reversal methods of either neostigmine and glycopyrronium or edrophonium and atropine.[7] They found that the time to TOF ratio of 0.9 was significantly reduced with sugammadex compared with either of the other two methods. In addition, the use of neostigmine was associated with a greater rise in heart rate and patients in both the neostigmine and edrophonium groups had a greater incidence of dry mouth.

Drug interactions
There is the theoretical possibility that sugammadex could engulf molecules other than the target NMBA. This has the potential to lead to two types of interaction. The first interaction, where a nontarget drug displaces the NMBA from sugammadex, would lead to reoccurrence of the blockade, and the second where another drug is also engulfed would lead to a reduction in activity of that drug. The SMPC describes the potential for toremifene, flucloxacillin and fusidic acid to displace either rocuronium or vecuronium from the binding site, resulting in prolongation of the recovery time.[3] It also describes the potential for sugammadex to remove a proportion of progestogen from the circulation: if a patient were taking the hormonal contraceptive this would be equivalent to missing a single daily dose.

Adverse effects
The safety profile of sugammadex appears to be very favourable. The most commonly reported side-effect is dysgeusia (bitter or metallic taste). There have been reports of lightening of the anaesthesia level. A case report by Molina et al describes a patient who was given an accidental 10-fold overdose but suffered no adverse effects.[8] Intriguingly, the FDA after initially assigning the drug priority status for a new drug application issued an action letter regarding the application.[9] Thepress release states that the letter relates to “issues concerning hypersensitivity/allergic reactions”.

Role in practice
At the end of July 2008 the European Medicines Agency approved sugammadex for use within the European Union.[10] The therapeutic indication given is reversal of neuromuscular blockade by rocuronium or vecuronium. Studies show that sugammadex produces a far more rapid reversal of neuromuscular blockade than traditional methods. It also appears from the studies to have a favourable safety profile. The recommended list price of the drug has turned out to be more expensive than the established treatment of neostigmine and
glycopyrronium.

The balance will need to be assessed between the older drugs, where the action and adverse effect profile are well known and this newer molecule, which is less well known by the practitioners who will use it. With the drive towards day surgery and shorter stays, a more predictable and safer drug may have the edge over older drugs. Conversely, in cases where the patient may need to return to theatre, sugammadex may be inappropriate as the indications are that a residual effect remains for some time after the dose is administered.

Ultimately, as it is used in practice the weight these factors carry will become clearer and the role of suggamadex will become more clearly defined. It remains, however, a unique and intriguing molecule.

References
1. Naguib M. Anesth Analg 2007;104:575—81.
2. Knaggs R. Hospital Pharmacy Europe 2008;40:21-2.
3. Bridion. Summary of product characteristics. Available at: http://www.bridion.com/HCP/About_Bridion/Prescribing_Information/index.asp
4. Shields M, Giovannelli M, Mirakhur RK, Moppett I, Adams J, Hermens Y. Br J Anaesth 2006;96(1):36-43.
5. Groudine SB, Soto R, Lien C, Drover D, Roberts K. Anesth Analg 2007;104:555—62.
6. de Boer HD, van Egmond J, van de Pol F, Bom A, Driessen JJ, Booij LHDJ. Br J Anaesth 2006;97(5):681-6.
7. Sacan O, White PF, Tufanogullari B, Klein K. Anesth Analg 2007;104:569-74.
8. Molina AL, de Boer HD, Klimek M, Heeringa M, Klein J. Br J Anaesth 2007;98(5):624-7.
9. Schering-Plough. US FDA issues action letter for sugammadex. Available at: http://www.scheringplough.com/news/news_article.aspx?reqid=1182475
10. Schering-Plough. BRIDION(R) (sugammadex) injection — first and only selective relaxant binding agent — approved in European Union. Available at: http://www.scheringplough.com/news/news_article.aspx?reqid=1180933

 



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