Sugammadex

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.

The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complexbound 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 anaesthetized patients with normal renal function the elimination half-life (t_1/2) of sugammadex is about 2 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 a pharmacokinetic study comparing patients with severe renal impairment to patients with normal renal function, sugammadex levels in plasma were similar during the first hour after dosing, and thereafter the levels decreased faster in the control group. Total exposure to sugammadex was prolonged, leading to 17-fold higher exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal insufficiency.

In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, sugammadex clearance progressively decreased and t_1/2 was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal insufficiency.

A summary of sugammadex pharmacokinetic parameters stratified by age and renal function is presented below:

^* CV = coefficient of variation

Gender

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.

Obesity

In one clinical study in morbidly obese patients, sugammadex 2 mg/kg and 4 mg/kg was dosed according to actual body weight (n=76) or ideal body weight (n=74). Sugammadex exposure increased in a dose-dependent, linear manner following administration according to actual body weight or ideal body weight. No clinically relevant differences in pharmacokinetic parameters were observed between orbidly obese patients and the general population.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity potential, and toxicity to reproduction, local tolerance or compatibility with blood.

Sugammadex is rapidly cleared in preclinical species, although residual sugammadex was observed in bone and teeth of juvenile rats. Preclinical studies in young adult and mature rats demonstrate that sugammadex does not adversely affect tooth colour or bone quality, bone structure, or bone metabolism. Sugammadex has no effects on fracture repair and remodelling of bone.