First selective relaxant binding agent Sugammadex: Clinical Pharmacology

Yoshiaki Uda 5/8/2011

Pharmaceutic aspects

Su refers to sugar and gammadex refers to the structural molecule gammacyclodextrin three-dimensional structures resemble a hollow, truncated cone or a doughnut. The structure has a hydrophobic cavity and a hydrophilic exterior

Expensive!
Large molecular weight 2178 a clear and colourless to slightly yellow solution in 2 mL/5 mL vials.

100 mg/mL, hydrochloric acid and sodium hydrochloride for pH adjustment

and Water for Injections. The pH is between 7 and 8 and osmolality is between 300 and 500 mOsm/kg. Marketed as Bridion

Clinical use
Rescue reversal When suxmethonium is contraindicated in RSI Muscular disorder ?rocuronium induced anaphylaxix

Dosage

Mechanism of action

formation of very tight complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium >> pancuronium)

rapid removal of free rocuronium molecules from the plasma a concentration gradient favoring the movement of the remaining rocuronium molecules from the neuromuscular junction back into the plasma increase in the total plasma concentration of rocuronium (both free and bound to sugammadex) Note: no effect on acetylcholinesterase or any receptor system in the body Ineffective against suxamethonium, benzylisoquinolinium neuromuscular blocker

Pharmacokinetic
Low protein binding Limited volume of distribution 10-18L Negligible transfer across placenta/BBB Sugammadex itself is excreted unchanged renally 65-97% of Sugammadex-rocuronium complex is eliminated renally Clearance of sugammadex or the complex is reduced in renal failure

Clinical efficacy
Compared to neostigmine More reliable, rapid reversal of neuromuscular blockade One RCT 4mg/kg sugammadex vs Neostigmine 70mcg/kg at 1-2 PTC recovery to T4/T1 ratio 2min40sec vs 49min. Dose dependent reversal of intense blockade. No ceiling effect Less chance of recularization, if used in dose >2mg.kg. Avoid side effects of anticholinesterase anticholinergic must be given bradycardia/bronchochonstriction, n+V, anastomosis issue (inc gut motility), 1.2mg of rocuronium followed by 16mg/kg sugammadex vs 1mg/kg suxmethonium Mean times to recovery of first twitch (T1) to 10% and T1 to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively) compared with the succinylcholine group (7.1 and 10.9 min

Compared to suxmethonium

Safety and tolerability

During clinical development Observed Rare (0.4%) side effects: QT prolongation, bronchospasm, respiratory failure, hypotension, AF. Rare allergy. Possible interaction with beta-lactam, steroid antibiotics, selective estrogen receptor modulator (tamoxifen) Use in renal falure, GFR<30ml/min discouraged Use in pregnancy category B2 Use in children limited safety/efficacy data in age <2. 217year for routine reversal of rocuronium (reapperance of T2) 2mg/kg. For immediate reversal, limited data to date.