Population pharmacokinetic–pharmacodynamic analysis for sugammadex‐mediated reversal of rocuronium‐induced neuromuscular blockade

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacokinetics and pharmacodynamics of rocuronium are well known.• A mechanistical pharmacokineticpharmacodynamic model based on limited data describing rocuronium and sugammadex pharmacokinetics has been published.• However, the available pharmacokineticpharmacodynamic model for the effects of sugammadex on rocuronium-induced neuromuscular blockade has limited predictive power. WHAT THIS STUDY ADDS• A pharmacokinetic-pharmacodynamic model is described for rocuronium and sugammadex, based on physiological principles and on data covering a wide range of ages and renal function. From this model, more accurate predictions can be made about sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade, in unexplored regimens or populations. AIMSAn integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODSData (n = 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTSSugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg -1 3 min after rocuronium, sugammadex 4 mg kg -1 during deep neuromuscular blockade and sugammadex 2 mg kg -1 during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONSSimulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min.

Sugammadex Ideal Body Weight Dose Adjusted by Level of Neuromuscular Blockade in Laparoscopic Bariatric Surgery

“…16 In a first step, sugammadex captures free rocuronium, leading to release of rocuronium from cell receptors; the released blocking agent is then bound to sugammadex. Even though the pharmacokinetic profile of sugammadex is affected by age and renal function, 24 quick reversal (less than 2 min) occurs in lean patients after a sugammadex dose of 2 mg/kg (moderate blockade) or 4 mg/kg (deep blockade), either with propofol or sevofluorane for anesthesia maintainance 24 -26 ; increasing the dose does not hasten recovery, and an effect plateau is seen in most patients around 2 min. 24 -26 However, outliers and slow responders have been detected when sugammadex is administered after a moderate and deep blockades.…”

“…24 -26 However, outliers and slow responders have been detected when sugammadex is administered after a moderate and deep blockades. 17,18,24,25 This issue, the presence of outliers, is of concern because it is related to potentially serious complications. Even after a TOFR of 0.9 or more has been achieved, upper airway weakness and an obstructive pattern have been observed in outlier patients.…”

The Myth of Rescue Reversal in “Can’t Intubate, Can’t Ventilate” Scenarios

“…12 Pharmacokinetic models for rocuronium and sugammadex accounted for age and used allometric scaling to account for size in model parameter predictions. Predictions of effect-site concentrations and drug effect for succinylcholine were made with published pharmacokinetic and pharmacodynamic models.…”

Cyclodextrins

“…As an example, it was observed that after IV bolus administration (10 mg kg The b-CD steady-state volume of distribution (V dss ) and most of its derivatives in all animal species tested correspond well with the respective extracellular fluid volume (Table 7). Thus, it can be concluded that, after IV administration, CDs distribute mainly in the extracellular compartments without involving the deep compartments or storage pools (Kleijn et al 2011). Methylated b-CD has a larger V dss and longer t ½ compared to other CD derivatives which may be due to its ability to interact with cellular membranes and its hemolytic activity (Thompson 1997).…”