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Pharmacology: Pharmacodynamics: Mechanism of action: Sugammadex is a modified gamma cyclodextrin which is a Selective Relaxant Binding Agent. It forms a complex with the neuromuscular blocking agents rocuronium or vecuronium in plasma and thereby reduces the amount of neuromuscular blocking agent available to bind to nicotinic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium or vecuronium.
Pharmacodynamic effects: Sugammadex has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response studies of rocuronium induced blockade (0.6, 0.9, 1.0 and 1.2 mg/kg rocuronium bromide with and without maintenance doses) and vecuronium induced blockade (0.1 mg/kg vecuronium bromide with or without maintenance doses) at different time points/depths of blockade. In these studies a clear dose-response relationship was observed.
Clinical efficacy and safety: Sugammadex can be administered at several time points after administration of rocuronium or vecuronium bromide: Routine reversal - deep neuromuscular blockade: In a pivotal study patients were randomly assigned to the rocuronium or vecuronium group. After the last dose of rocuronium or vecuronium, at 1-2 PTCs, 4 mg/kg sugammadex or 70 mcg/kg neostigmine was administered in a randomised order. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was: Time (minutes) from administration of sugammadex or neostigmine at deep neuromuscular blockade (1-2 PTCs) after rocuronium or vecuronium to recovery of the T4/T1 ratio to 0.9. (See Table 1.)
Click on icon to see table/diagram/imageRoutine reversal - moderate neuromuscular blockade: In another pivotal study patients were randomly assigned to the rocuronium or vecuronium group. After the last dose of rocuronium or vecuronium, at the reappearance of T2, 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered in a randomised order. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was: Time (minutes) from administration of sugammadex or neostigmine at reappearance of T2 after rocuronium or vecuronium to recovery of the T4/T1 ratio to 0.9. (See Table 2.)
Click on icon to see table/diagram/imageReversal by sugammadex of the neuromuscular blockade induced by rocuronium was compared to the reversal by neostigmine of the neuromuscular blockade induced by cis-atracurium. At the reappearance of T2 a dose of 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered. Sugammadex provided faster reversal of neuromuscular blockade induced by rocuronium compared to neostigmine reversal of neuromuscular blockade induced by cis-atracurium: Time (minutes) from administration of sugammadex or neostigmine at reappearance of T2 after rocuronium or cis-atracurium to recovery of the T4/T1 ratio to 0.9. (See Table 3.)
Click on icon to see table/diagram/imageFor immediate reversal: The time to recovery from succinylcholine-induced neuromuscular blockade (1 mg/kg) was compared with sugammadex (16 mg/kg, 3 minutes later) - induced recovery from rocuronium-induced neuromuscular blockade (1.2 mg/kg). Time (minutes) from administration of rocuronium and sugammadex or succinylcholine to recovery of the T1 10%. (See Table 4.)
Click on icon to see table/diagram/imageIn a pooled analysis the following recovery times for 16 mg/kg sugammadex after 1.2 mg/kg rocuronium bromide were reported: Time (minutes) from administration of sugammadex at 3 minutes after rocuronium to recovery of the T4/T1 ratio to 0.9, 0.8 or 0.7. (See Table 5.)
Click on icon to see table/diagram/imageRenal impairment: Two open label studies compared the efficacy and safety of sugammadex in surgical patients with and without severe renal impairment. In one study, sugammadex was administered following rocuronium induced blockade at 1-2 PTCs (4 mg/kg; N=68); in the other study, sugammadex was administered at reappearance of T2 (2 mg/kg; N=30). Recovery from blockade was modestly longer for patients with severe renal impairment relative to patients without renal impairment. No residual neuromuscular blockade or recurrence of neuromuscular blockade was reported for patients with severe renal impairment in these studies.
Effects on QTc interval: In 3 dedicated clinical studies (N=287) with sugammadex alone, sugammadex in combination with rocuronium or vecuronium, and sugammadex in combination with propofol or sevoflurane were not associated with clinically significant prolongation of the QT/QTc interval. The integrated electrocardiogram and adverse event results of the Phase 2-3 studies support this conclusion.
Pharmacokinetics: The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound sugammadex in anaesthetised subjects.
Distribution: The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 litres in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose.
Metabolism: In preclinical and clinical studies no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination.
Elimination: In adult anaesthetised patients with normal renal function the elimination half-life (t½) of sugammadex is about 1.8 hours and the estimated plasma clearance is about 88 mL/min. A mass balance study demonstrated that >90% of the dose was excreted within 24 hours. 96% of the dose was excreted in urine, of which at least 95% could be attributed to unchanged sugammadex. Excretion via faeces or expired air was less than 0.02% of the dose. Administration of sugammadex to healthy volunteers resulted in increased renal elimination of rocuronium in complex.
Special populations: Renal impairment and age: In two pharmacokinetic studies comparing patients with severe renal impairment to patients with normal renal function, plasma concentrations of sugammadex were similar for at least the first 20 minutes after dosing and then declined more rapidly than in controls. Total exposure to sugammadex was prolonged, resulting in approximately 15-fold higher exposure in patients with severe renal impairment. In some patients with severe renal impairment, sugammadex concentrations were minimally detectable in plasma after 1 month of dosing.
The pharmacokinetic parameters of sugammadex predicted by age group and renal function based on the compartmental model (using 3 compartments) are presented as follows: See Table 6.
Click on icon to see table/diagram/imageGender: No gender differences were observed.
Race: In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data does not indicate differences in pharmacokinetic parameters in Black or African Americans.
Body weight: Population pharmacokinetic analysis of adult and elderly patients showed no clinically relevant relationship of clearance and volume of distribution with body weight.
