( A Path to Ultra-short acting non-depolarisers )

Sugammadex

Dr Howard Machlin Department of Anaesthesia & Perioperative Medicine Alfred Hospital

!The first administration of curare to produce surgical relaxation occurred in 1912 (Arthur Lwen German surgeon in Leipzig) !d-tubocurarine was introduced into clinical practice in 1942 !More than a dozen agents have been introduced since then each with Different onset of action, duration of action & CV safety profile !A major issue is the recovery of neuromuscular blockade

Neuromuscular Blockade
The nicotinic receptor at the NMJ Ach must bind to the 2 ! subunits simultaneously to induce a conformational change.

Neuromuscular Blockade
Nondepolarising Depolarising
Succinylcholine Associated with many S/E Use relatively C/I in patients with burns, muscle disorders, neurological disease and a Hx of trauma Bind competitively to ! subunit without producing any ionic current or depolarisation Benzylisoquinolones (atracurium, cisatracurium, mivacurium) Molecules with steroid nucleus (pancuronium, rocuronium, vecuronium)

Neuromuscular Blockade
Only a few drugs remain popular Most with significant CV S/E, histamine release or long duration of action have been virtually eliminated PORC remains a problem
(Postoperative residual curarisation)

The PORC problem

Murphy GS et al incomplete n-m recovery is an important contributing factor in the development of adverse respiratory events in the PACU. These events occurred despite;
Intraoperative monitoring to guide degree of n-m relaxation and to guide adequacy of reversal Administration of neostigmine Delivery of care by knowledgeable clinicians
(Murphy GS et al. Residual Neuromuscular Blockade & Critical Respiratory Events in the PACU. Anesthesia & Analgesia 107 (1) 130-137 July 2008)

PORC Avoidance
Use short acting agent NMBA titrated to aim for full recovery of n-m function at completion of surgery Accelerate recovery of n-m function
Anticholinesterase agents (neostigmine, edrophonium & pyridostigmine)
Naguib M et al. Neuromuscular monitoring & postoperative residual curarization: a metaanalysis BJA 98 (3) 302-16 (2007)

Anticholinesterases
Inhibit Ach hydrolysis at extramuscular sites leading to untoward muscarinic parasympathetic effects (bradycardia,
bronchoconstriction, increased peristalsis)

Require concurrent administration of anti-cholinergic agents A major limitation is their ceiling effect (most likely at doses corresponding to acetylcholinesterase inhibition approaching 100%)

Rather than restore the function of the NMJ by increasing the amount of agonist perhaps an agent could be used to chelate or bind or inactivate the molecules of the NMBA that bind to the receptor

Cyclodextrins
Have been used for > 50yrs to solubilise lipophilic molecules, including steroidal molecules If rocuronium preferentially entered the lipophilic cavity of the cyclodextrins & a way could be found to keep Rocuronium inside the cavity then a potent reversal agent could be developed ORG 25969 or SUGAMMADEX is a modified "-cyclodextrin (Su
refers to sugar & gammadex refers to the structural molecule "-cyclodextrin)

Cyclodextrins
Ring shaped molecules made up of 6 8 sugars
!-cyclodextrins include 6 sugars, #-cylcodextrins have 7 sugars, & "-cyclodextrins have 8 sugars

Their 3-D structures resemble a hollow, truncated cone or a doughnut The structure has a hydrophobic cavity and a hydrophilic exterior. Hydrophobic interactions trap the drug into the cyclodextrin cavity " soluble guest-host complex water

Sugammadex
Unmodified "-cyclodextrin is not deep enough to accommodate the larger rigid structure of the rocuronium molecule 8 side chains were added to extend the cavity to better accommodate the 4 hydrophobic steroidal rings of rocuronium Negatively charged carboxyl groups were added at the end of the side chains to enhance electrostatic binding to the positively charged quarternary nitrogen of rocuronium

Sugammadex

Radiograph crystal structure of a rocuronium molecule (A) and a sugammadex molecule (B)

Naguib, M. Anesth Analg 2007;104:575-581

Encapsulation of rocuronium molecule (blue) by a sugammadex molecule (green) at 1:1 ratio

Naguib, M. Anesth Analg 2007;104:575-581

Sugammadex -1
st

Selective relaxant binding agent (SRBA)

Exerts its effect by forming very tight complexes (1:1 ratio) with steroidal NMBAs (Roc > Vec >> Panc) The guest-host complex exists in equilibrium with a very high association rate and a very low dissociation rate During rocuronium induced n-m blockade the IV administration of sugammadex results in rapid removal of free rocuronium molecules from the plasma

 Initial experiments were performed in the mouse phrenic nervehemidiaphragm preparation The effectiveness was tested in guinea pigs & cats In monkeys sugammadex has no CVS effects & is well tolerated Sugammadex is not effective against blockade produced by benzylisoquinolone drugs.

The next phase human volunteers

Sugammadex
Effectiveness is dose dependent With 0.6 mg/kg Rocuronium at induction T2 appears after 3045min Rapid (1-3min) return of TOFR to > 0.9 requires 2-4 mg/kg Sugammadex Spontaneous recovery takes 30-60 min

Sugammadex
Reversal with sugammadex has been attempted at deep levels of blockade (PTC = 2) Doses required were found to be greater than at reapperance of T2 Sugammadex 8-16mg/kg may be required for a 1-3 min return of TOFR > 0.9

Sugammadex

Reversal of profound high dose rocuronium induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose finding, safety assesor-blinded, phase II trial.
(Phringer FK et al. Anesthesiology 2008 Aug;109(2): 188-97)

Sugammadex- phase 3
AURORA SIGNAL SPECTRUM VISTA

Sugammadex (2.0mg/kg) reverses shallow ROC-induced NMB significantly faster compared with neostigmine (50!g/kg)

AURORA

SIGNAL
Faster reversal of profound Roc induced NMB with Sugammadex vs Neostigmine

SPECTRUM
Reversal of profound Roc induced NMB with sugammadex is faster than recovery from Succinylcholine

VISTA
Sugammadex given at least 15 min after Roc is effective in reversing NMB

Questions to be resolved
Sugammadex is excreted via the kidney
Stalls LM BJA 23 July 2008

Use in the presence of neuro-muscular disease Drug interactions Requirement for re-paralysis

Concerns
Many more patient exposures are required to fully appreciate the drugs risk profile The last 15 yrs has seen a significant reduction in the use of NMBA. There is no best evidence that profound NMBA improve outcome Increased cost

Side effects
Not dose related 14% of patients experienced an AE considered to be possibly, probably or definitely drug related 12 patients (sugammadex=11, & placebo=1) suffered a serious AE

Current status
!Approved by the European Union on July 29 2008

FDA rejected the application on 1 August 2008, citing concerns regarding hypersensitivity/allergic reactions ( despite a unanimous recommendation for approval by the FDA Advisory Committee on Anesthetics and Life Support in March 2008)

References
Naguib M. Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth & Analg. 2007;104:575-58 Donati F. Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia. Expert Opin Pharmacother. 2008 Jun; 9(8):1375-86. Review Vanacker BF et al. Reversal of rocuronium induced neuromuscular block with the novel drug sugammadex is equally effective under maintenance anaesthesia with propofol or sevoflurane. Anesth Analg. 2007;104:563-8 Sacan O et al. Sugammadex reversal of rocuronium induced neuromuscular blockade: a comparison with neostigmine glycopyrolate & edrophonium-atropine. Anesth Analg 2007;104:569-74 Sorgenfrei IF et al. Reversal of rocuronium induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose finding and safety study. Anesthesiology 2006;104:667-74 Groudine SB et al A randomized, does-finding, phase II study of the selective relaxant binding drug, sugammadex, capable of safely reversing profound rocuronium induced neuromuscular block. Anesth Analg 2007; 104:555-62

 References
Sheilds M et al. Org 25969 (sugammadex), a selective relaxant binding agent for antagonism of prolonged rocuronium induced neuromuscular block. Br J Anaesth 2006;96:36-43 Blobner M et al. Sugammade (2.0 mg/kg) reverses shallow rocuronium induced neuromuscular blockade significantly faster compared with neostigmine (50$g/kg). The AURORA trial. Poster presentation. 14th WCA March 2-7 2008, Cape Town, South Africa. Jones R et al. Faster reversal of profound rocuronium induced neuromuscular blockade with sugammadex versus neostigmine. The SIGNAL trial. Poster presentation. 14th WCA March 2-7 2008, Cape Town, South Africa. Lee C et al. Reversal of profound rocuronium induced neuromuscular block with sugammadex is faster than recovery with succinylcholine. The SPECTRUM trial. Poster presentation. 14th WCA March 2-7 2008, Cape Town, South Africa. Pavlin E et al. Sugammadex given at least 15 minutes after rocuronium is effective in reversing neuromuscular blockade. The VISTA trial. Poster presentation ASA meeting October 13-17 2007, San Francisco