Repeat dosing of rocuronium-sugammadex: unpredictable

provided the original work is properly cited. CC Like many other great discoveries, sugammadex was discovered incidentally. Anton Bom, a pharmaceutical chemist employed by Organon, Inc., was attempting to identify a new solvent that could enhance the solubility of rocuronium bromide. Instead, he was the first to discover that long-term use of cyclodextrin as a solubilizing agent offset the potency of rocuronium. The three-dimensional structure of cyclodextrin resembles a hollow or doughnut. The structure contains a hydrophobic cavity and hydrophilic exterior because of the presence of polar hydroxyl groups. Hydrophobic interactions trap the drug within the cyclodextrin cavity, resulting in the formation of a water-soluble guest-host complex. Sugammadex was developed by adding negatively charged carboxyl groups to each end of the side chain, thus increasing the electrostatic binding force with the positively charged rocuronium, and by adding eight side chains to encapsulate the relatively large-sized rocuronium [1,2]. Interestingly, sugammadex acts much like Febreze, an odor-controlling agent commonly used within the home. Sugammadex, the first selective relaxant-binding agent, acts by tightly binding to steroidal neuromuscular blocking agents through intermolecular forces and thermodynamic and hydrophobic interactions [3]. Introduction of sugammadex to the field of anesthesia was termed “a milestone” [3], “a revolutionary approach” [4], and “a turning point in the practice of anesthesiology” [5]. Anesthesiologists were enormously enthusiastic about this new drug. In fact, since the emergence of sugammadex, no revolutionary novel drugs have been developed for the last 20 years. Additionally, because of the many limitations of the anticholinesterases commonly used as reversal agents after the administration of neuromuscular blockers, anesthesiologists were in need of a drug that could reverse neuromuscular blockade in a short period of time. After sugammadex is injected, it rapidly binds with free rocuro nium molecules in the plasma, leading to a decrease in the rocuronium plasma concentration. Thus, a rocuronium concentration gradient is formed between the plasma and neuromuscular junction, and rocuronium is released from the neuromuscular junction to the plasma, where it can also bind with sugammadex [2]. Available evidence suggests that the rocuronium-sugammadex complex remains stable over time. This complex exists in equilibrium with a very low dissociation rate (dissociation constant Kd = 0.1 × 10 M) because of the strong binding [3,6]. The molecular weight of sugammadex is 2,178 Da, while that of rocuronium is 610 Da; the two molecules bind in a 1 : 1 molar ratio. Thus, precisely 3.57 mg of sugammadex are required to bind 1.00 mg of rocuronium [3,6]. Accordingly, we can conclude that effective reversal is guaranteed by injection of 2.4 mg/kg of sugammadex at any time after injection of 0.6 mg/kg of rocuronium [7]. In the dose range of 0.1 to 16.0 mg/kg, the pharmacokinetics of sugammadex show a linear, dose-dependent relationship [2]. Sugammadex (0.1-8.0 mg/kg) has a clearance rate of 88 ml/min, elimination half-life of 1.8 h, and distribution volume of 11 to 14 L [8,9]. Approximately 75% of the dose is eliminated renally; 59-80% of the dose is excreted renally in the first 24 h after administration [8]. After encapsulation by sugammadex, rocuronium is confined to the space in which sugammadex resides, and urinary excretion is the main route of elimination of the sugammadex-rocuronium complex. Administration of sugammadex diverts the elimination of rocuronium from its normal primary pathway of hepatic clearance to renal clearance [8]. Sugammadex is a very safe drug with almost no serious adverse