Sugammadex ( A Path to Ultra-short acting non-depolarisers ) 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 blockadeNeuromuscular Blockade The nicotinic receptor at the NMJ Ach must bind to the 2 ! subunits simultaneously to induce a conformational change. Neuromuscular Blockade Nondepolarising Bind competitively to ! subunit without producing any ionic current or depolarisation Benzylisoquinolones (atracurium, cisatracurium, mivacurium) Molecules with steroid nucleus (pancuronium, rocuronium, vecuronium) Depolarising Succinylcholine Associated with many S/E Use relatively C/I in patients with burns, muscle disorders, neurological disease and a Hx of traumaNeuromuscular 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 Beecher & Todd 1954 where muscle relaxants are involved an appreciable increase in the anesthesia date rate is presented. 63% of the curare deaths were caused by respiratory failure (Brull SJ et al. Residual Neuromuscular Block: Rediscovering the Obvious Anesthesia & Analgesia 107 (1): 11-14 July 2008) 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 " water soluble guest-host complex 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 rocuroniumSugammadex Naguib, M. Anesth Analg 2007;104:575-581 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 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 volunteersSugammadex 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 > 0.9Sugammadex 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

AURORA Sugammadex (2.0mg/kg) reverses shallow ROC-induced NMB significantly faster compared with neostigmine (50!g/kg)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 SuccinylcholineVISTA 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-paralysisConcerns 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 AECurrent 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. 14 th 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. 14 th 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. 14 th 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 FranciscoSugammadex ( A Path to Ultra-short acting non-depolarisers ) 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 blockadeNeuromuscular Blockade The nicotinic receptor at the NMJ Ach must bind to the 2 ! subunits simultaneously to induce a conformational change. Neuromuscular Blockade Nondepolarising Bind competitively to ! subunit without producing any ionic current or depolarisation Benzylisoquinolones (atracurium, cisatracurium, mivacurium) Molecules with steroid nucleus (pancuronium, rocuronium, vecuronium)

 Depolarising Succinylcholine Associated with many S/E Use relatively C/I in patients with burns, muscle disorders, neurological disease and a Hx of traumaNeuromuscular 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 Beecher & Todd 1954 where muscle relaxants are involved an appreciable increase in the anesthesia date rate is presented. 63% of the curare deaths were caused by respiratory failure (Brull SJ et al. Residual Neuromuscular Block: Rediscovering the Obvious Anesthesia & Analgesia 107 (1): 11-14 July 2008) 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 " water soluble guest-host complex 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 rocuroniumSugammadex Naguib, M. Anesth Analg 2007;104:575-581 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 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 volunteersSugammadex 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 > 0.9Sugammadex 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 AURORA Sugammadex (2.0mg/kg) reverses shallow ROC-induced NMB significantly faster compared with neostigmine (50!g/kg)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 SuccinylcholineVISTA 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-paralysisConcerns 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 AECurrent 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. 14 th 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. 14 th 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. 14 th 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 Franciscov