Sugammadex for the reversal of rocuronium induced deep neuromuscular blockade in patients with severe renal impairment: Incorporation of findings from a phase IIIb, multicentre, parallel group, comparative clinical trial evaluating the efficacy, pharmacokinetics and safety of sugammadex 4.0mg/kg administered at 1-2 post tetanic count in subjects with normal or severely impaired renal function

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Abstract

Title: Sugammadex for the reversal of rocuronium induced deep neuromuscular blockade in patients with severe renal impairment.Background: Sugammadex is a selective relaxant binding agent which can encapsulate and thus rapidly reverse the action of the neuromuscular blocking agent rocuronium. Sugammadex and the sugammadex-rocuronium complex are excreted via renal pathways therefore patients with renal impairment may experience differences in drug action compared to controls. To investigate any differences, this study was designed to evaluate the efficacy, safety and pharmacokinetics of sugammadex given for reversal deep neuromuscular blockade, in patients with and without severe renal impairment. Methods: Adult patients received intravenous (IV) anaesthesia with remifentanil and propofol. Neuromuscular function monitoring was then implemented, using acceleromyography at the adductor pollicis muscle using the TOF-Watch® SX, V1.6. Rocuronium 0.6mg/kg iv was given to facilitate tracheal intubation and further doses of rocuronium 0.1-0.2mg/kg iv were given to ensure deep neuromuscular blockade as measured by a post tetanic count (PTC) of 1-2. When surgery was completed and the PTC measured 1-2, a single IV bolus of sugammadex 4.0mg/kg was administered. The primary efficacy data collected was time to recovery of the train of four (TOF) ratio≥0.9. Blood samples were taken for safety, pharmacokinetic and dialysis data from the day of surgery to the 28 day assessment window. Serious/adverse event data were collected according to ICHGCP guidelines. Further safety data were collected on signs of recurrence of neuromuscular blockade, and vital signs throughout the trial period.Results: Our study centre treated 16 patients out of 68 treated in the entire study. In our study centre the geometric mean time from start of administration of sugammadex to recovery of the TOF ratio≥0.9 was 176 sec (95% confidence interval (CI):112-278) for the renal group and 50 sec (95% CI: 30-83) for the control group. Non-parametric analysis indicated that equivalence in efficacy of sugammadex could not be claimed. Post hoc Wilcoxon rank sum test demonstrated statistically significant differences between the control and renal groups for time of start of sugammadex administration to time of TOF ratio≥ 0.9 (p=0.004). Results of the efficacy analysis were similar in the entire study population. Comparison of pharmacokinetic parameters of sugammadex showed statistically significant differences (Student t-test p<0.001) between the groups with increased exposure to sugammadex in the renal group; geometric mean AUC 0-∞ μg.min/ml (coefficient of variation) control group 3985 (20.7), renal group 28569 (27.8) p<0.001.There were no incidences of recurrence of neuromuscular blockade in either group and there appeared to be no difference in the safety profile between the groups. Conclusions: Reversal of rocuronium induced neuromuscular blockade by sugammadex is likely to be slower and exposure to sugammadex longer in patients with severe renal impairment when compared to healthy controls. In patients with severe renal impairment, sugammadex has been shown to reverse deep neuromuscular blockade efficaciously i.e. no recurrence of neuromuscular blockade, and in a clinically useful timeframe when considering other methods of reversal of blockade. Further work, comparing the use of sugammadex in patients and controls, both with renal failure, will allow more valid pharmacokinetic and safety comparisons to be made.

Keyword(s)

neuromuscular blockade; renal; renal failure; reversal; reversal neuromuscular blockade; rocuronium; sugammadex

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