Conditions: Anesthesia, General Neuromuscular Blockade
Keywords: sugammadex pharmacokinetics pharmacodynamics pediatric anesthesia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This study administers sugammadex sodium to pediatric patients under general anesthesia with rocuronium. Pharmacokinetic and pharmacodynamic analysis are performed based on plasma concentration of sugammadex sodium and monitoring of neuromuscular blockade.

Detailed description:
This study enrolls pediatric patients undergoing surgery under general anesthesia with need for early reversal of neuromuscular blockade, aged between 2 and 18 years old.

After routine anesthetic induction with 1% propofol and 0.6mg/kg of rocuronium, maintenance of anesthesia with total intravenous anesthesia is commenced. 15 minutes after rocuronium administration, 2 or 4 or 8mg/kg of sugammadex sodium or conventional neuromuscular reversal agent is administered according to randomization table.

For neuromuscular monitoring, train-of-four (TOF) count and T4/T1 ratio are monitored, with recording of the time to recovery of the T4/T1 ratio to 0.7, 0.8 and 0.9.

For pharmacokinetic analysis, patient blood sample is obtained before / 2 min after rocuronium administration, before / 2min / 5min / 15min / 60min / 120min / 240min / 480min after sugammadex administration. Plasma concentration of rocuronium and sugammadex sodium are analyzed via high-performance liquid chromatography with mass spectrometric detection.

Arms:
arm 1: Administer 2mg/kg of sugammadex 15 minutes after rocuronium administration arm 2: Administer 4mg/kg of sugammadex 15 minutes after rocuronium administration arm 3: Administer 8mg/kg of sugammadex 15 minutes after rocuronium administration arm 4: Administer conventional neuromuscular reversal agent (0.02mg/kg of atropine and 0.03mg/kg of neostigmine) 15 minutes after rocuronium administration

Interventions: intervention 1: Sugammadex Injection 2mg/kg intervention 2: Sugammadex Injection 4mg/kg intervention 3: Sugammadex Injection 8mg/kg intervention 4: Neuromuscular reversal agent injection
Intervention descriptions: intervention 1: Intravenous injection of 2mg/kg of sugammadex sodium 15 minutes after rocuronium administration intervention 2: Intravenous injection of 4mg/kg of sugammadex sodium 15 minutes after rocuronium administration intervention 3: Intravenous injection of 8mg/kg of sugammadex sodium 15 minutes after rocuronium administration intervention 4: Intravenous injection of 0.02mg/kg of atropine and 0.03mg/kg of neostigmine

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
 
 
Study protocol and Statistical analysis plan of 
 
Pharmacokinetic-pharmacodynamic Analysis of Sugammadex in 
Children 
(NCT03943888) 
 
Document date: 06/19/2019 
 
 


2 
1) Study protocol 
STUDY DESIGN AND POPULATION 
This study was designed as a randomized, controlled, single-blinded, exploratory 
study to examine the pharmacokinetics of sugammadex and compare the 
pharmacodynamics of 2, 4, or 8 mg∙kg-1 of sugammadex against 0.03 mg∙kg-1 of 
neostigmine. This study was conducted at a single center. The study protocol was 
approved by the Institutional Review Board of the Seoul National University Hospital 
(1904-149-1029, approval date: 07/31/2019) and the Ministry of Food and Drug 
Safety of the Republic of Korea (approval no.: 32285, approval date: 07/09/2019). 
This study was registered at http://clinicaltrials.gov (NCT03943888, principal 
investigator: Hee-Soo Kim, published date: 08/13/2019). The study was conducted 
in accordance with the Good Clinical Practice guidelines by the International Council 
for Harmonization and the Declaration of Helsinki. Participants were recruited 
between August 2019 and February 2020. 
Children aged 2−17 years, with an American Society of Anesthesiologists (ASA) 
physical status classification of 1 or 2, who were scheduled to undergo surgery 
under general anesthesia, and required early reversal of neuromuscular blockade 
after induction because of electrophysiology monitoring were enrolled. Written 
informed consent was obtained from one parent of each participant aged younger 
than 7 years, whereas it was obtained from both the participant and one of their 
parents for children aged 7−17 years. The exclusion criteria were a history of 
hypersensitivity to any anesthetic agents including rocuronium; the presence of 
underlying cardiovascular or genitourinary disease; the use of a neuromuscular 
blocking agent or any other drug that can influence the effect of rocuronium before 
surgery; a history of malignant hyperthermia; anticipation of massive hemorrhage 
during surgery; and one or more parent or legal guardian declining to enroll. 
 
STUDY PROTOCOL 
 
Upon the participant’s arrival in the operating room, electrocardiogram (ECG), 
non-invasive blood pressure at 1-min intervals, and pulse oximetry for peripheral 
capillary oxygen saturation (SpO2) were monitored. Anesthesia was induced in a 


3 
routine manner with sodium thiopental or propofol according to age. Intravenous 
propofol and remifentanil were continuously infused to maintain anesthesia while 
providing 100% oxygen via a fitting mask. Train-of-four stimulation was performed 
with four twitch stimulations over 2 s with an intensity of 50 mA every 15s via 
ToFscan® (IDMED, Marseille, France) at the participant’s unilateral ulnar nerve. 
Responses to the train-of-four stimulations were measured by acceleromyography 
and automatically recorded via a program provided by the manufacturer. After the 
start of the recording, 1 mg∙kg-1 of rocuronium was intravenously injected. Arterial 
catheterization was performed at one of the four extremities, and continuous 
monitoring of blood pressure was initiated. After confirmation of a train-of-four 
count of zero, the post-tetanic count, which measures the number of responses to 
15 twitch stimulations at 50 Hz for 5 s, was measured at another extremity. After 
confirmation of zero post-tetanic count, the study drug was administered 
intravenously. At the end of the surgery, the train-of-four monitoring was stopped. 
 
PHARMACOKINETIC MEASUREMENTS 
 
Arterial blood was withdrawn nine times to measure the plasma 
concentrations of rocuronium and sugammadex at 2 min after rocuronium injection; 
immediately before study drug administration; and 2, 5, 15, 60, 120, 240, and 480 
min after study drug administration. The concentration of rocuronium was measured 
at every time point, whereas sugammadex was excluded at the first point. In case 
of deviation from the scheduled time, the actual time of sampling was recorded. 
 
MEASUREMENT OF PLASMA CONCENTRATIONS 
 
At the previously described time points, 1 mL of arterial blood was drawn 
for each measurement, and the blood was immediately stored in a sodium heparin 
tube (BD Vacutainer® sodium heparin (N) 75 USP Units, Becton Dickinson Korea, 
Seoul, Korea). After centrifuging the samples at 3,000 rpm for 10 min, the 
supernatant was collected and stored in a sterile internal cryogenic vial (CryotainTM, 
SCILAB Korea, Seoul, Korea). The cryovials were stored in a freezer below -70ºC until 
analysis. 


4 
Plasma concentrations of sugammadex and rocuronium were measured using 
liquid chromatography-tandem mass spectrometry. The assays were conducted in 
full compliance with the Good Laboratory Practice regulations. As this assay could 
not discriminate the sugammadex-rocuronium complex from their free forms, all 
plasma concentrations were considered total plasma concentrations. The internal 
standard was donepezil base for sugammadex and 3-acetyl rocuronium bromide for 
rocuronium, respectively (Toronto Research Chemicals, North York, Canada). The 
lower limit of quantification and upper limit of quantification were set as 0.1 and 
100 μg∙mL-1 for sugammadex and as 10 and 10,000 ng∙mL-1 for rocuronium. The 
intra-assay coefficient of variation was no more than 14.9%, and the % bias was -
12.5‒2.0% for sugammadex. The intra-assay coefficient of variation was no more 
than 5.7%, and the % bias was -5.6‒5.0% for rocuronium. 
 
2) Control group setting and randomization method 
According 
to 
a 
randomization 
table 
obtained 
from 
the 
website 
https://sealedenvelope.com/, the participants were allocated to one of the four 
groups: 2, 4, or 8 mg∙kg-1 of sugammadex or a control group with 0.03 mg∙kg-1 of 
neostigmine. According to the allocation, the study drug was prepared by a single 
anesthesiologist (J.H. Lee). The participants and their parents were blinded to the 
group allocation. 
 
3) Data analysis and statistical analysis method 
NONCOMPARTMENTAL ANALYSIS 
The noncompartmental pharmacokinetic parameters of sugammadex and 
rocuronium were calculated using a validated software, Phoenix WinNonlin (Version 
8.1; Certara USA, Princeton, NJ, USA). The maximum concentration (Cmax) and time 
to reach Cmax were determined from the observed values. The area under the 
plasma concentration-time curve (AUC) from time zero to the last measurable 
concentration (AUClast) was calculated using linear-up log-down trapezoidal method. 
Partial AUCs from time zero to 15 minutes (AUC0-15m) and 1 h post-dose (AUC0-1h) 
were calculated using the same method. AUC from time zero to infinity (AUCinf) was 
calculated as the sum of AUClast and the last measureable concentration divided by 


5 
terminal elimination constant (λz) estimated by linear regression. Terminal-phase 
elimination half-life (t1/2) was calculated as natural logarithm of 2 divided by λz. 
Clearance (CL) and terminal-phase volume of distribution (Vz) were calculated as 
Dose∙AUCinf-1 and Dose∙(λz ·AUCinf)-1. 
 
POPULATION PHARMACOKINETIC MODELING OF SUGAMMADEX 
Population pharmacokinetic model for sugammadex was developed using nonlinear 
mixed-effect modelling software (NONMEM 7.4.4 software, ICON Development 
Solutions, Ellicott City, MD, USA). Data processing and diagnostics were performed 
using R version 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria) and 
Perl-Speaks-NONMEM (version 4.9.0, https://uupharmacometrics.github.io/PsN/). 
Plasma concentrations were fitted into one/two/three-compartment models via the 
ADVAN 6 subroutine and first-order conditional estimation with interaction. During 
model building, inter-individual variabilities of parameters were assumed to be log-
normally distributed and introduced as exponential. The residual error was described 
with a proportional model. The minimum objective function value was obtained, 
which was equivalent to the -2 log likelihood of the model. For an alpha-error 
probability of 0.05, a reduction in the objective function value by more than 3.84 
was regarded as significant according to the χ2 distribution at degrees of freedom 
= 1. 
After determining the base pharmacokinetic models, covariates of age, sex, weight, 
height, and serum creatinine concentration5 were evaluated for selection. The effect 
of bodyweight on clearance was considered with allometric scaling as follows: 
Pi= θp × ((BWi)/(MeanBWi ))0.75×eηi 
where Pi denotes the individual value, θp represents the population estimates, BWi 
represents the individual bodyweight, and ηi denotes the inter-individual random 
effect. 
 After development, goodness-of-fit plots comparing observations and individual 
predictions, observations and population predictions, conditional weighted residuals 
and population predictions, conditional weighted residuals, and time after dosing 
were sketched. For internal validation, median values and their 95% confidence 
intervals for each parameter were obtained from a nonparametric bootstrap analysis 
of 1,000 simulated datasets. Prediction-corrected visual predictive check was 
performed with the R package ‘xpose’. The prediction-corrected visual predictive 
check evaluated whether the observed data were within the median and 90% 


6 
prediction interval of 1,000 simulated datasets from the final model. The models 
were executed, and diagnostics were performed using Pirana (version 2.9.9, 
https://www.pirana-software.com). 
During 
the 
modeling, 
the 
rocuronium-
sugammadex complex was not discriminated from the free form of sugammadex or 
rocuronium, since they were indistinguishable during the plasma concentration 
measurement. Referring to previous studies, we assumed elimination constant of 
rocuronium-sugammadex complex as identical to that of sugammadex and built a 
pharmacokinetic model of sugammadex, regardless of complex formation. 
 
PHARMACODYNAMIC MEASUREMENTS 
 
During or after surgery, neuromuscular blockade was monitored by 
evaluating the response to a peripheral nerve stimulation. Train-of-four stimulation, 
which consists of four successive supramaximal stimuli delivered at 2Hz on the ulnar, 
facial, or posterior tibial nerve, is the most common means of monitoring. The count 
of responses to the stimuli and the ratio of the fourth twitch to the first twitch (T4/T1 
ratio) represent the receptor occupancy by rocuronium. A T4/T1 ratio greater than 
90% is considered sufficient for extubation. Usually, the efficacy of the reversal agents 
for neuromuscular blockade is measured as the time after administration of reversal 
agents to recovery of the T4/T1 ratio greater than 90%. 
The count of twitches and the T4/T1 ratio to the train-of-four stimulations were 
automatically recorded until the end of the surgery and were compared according 
to the group. The time elapsed from the study drug administration to the attainment 
of a T4/T1 ratio ≥ 0.9 was the primary pharmacodynamic outcome. To bind the 
pharmacokinetics of sugammadex to pharmacodynamic measurements, the time to 
recovery of the train-of-four ratio larger than 0.9 was plotted against the Cmax and 
AUClast of sugammadex. 
 
MONITORING OF SAFETY 
 
Monitoring of the participants’ ECG, mean blood pressure, pulse oximetry, 
and body temperature was started from the beginning of anesthesia and continued 
until 24 h after the end of surgery. The presence of hemodynamic instability (more 
than 30% change from baseline for heart rate and mean blood pressure), hypoxemia 
(less than 92%), hyperthermia (above 38.3ºC), hypothermia (below 35.5ºC), nausea, 
vomiting, urticaria, and any anaphylactic reactions was monitored and recorded. 
 


7 
STATISTICAL ANALYSIS 
 
Data for the baseline characteristics and pharmacodynamics were tested for 
normality using the Kolmogorov−Smirnov test for data from the whole study 
population and the Shapiro−Wilk test for data from individual study groups. For 
nonparametric comparison of baseline characteristics of individual study groups, the 
Kruskal−Wallis test and a consequent Mann−Whitney U test with Bonferroni 
correction for post-hoc analysis were employed using the SPSS® version 22 (IBM®, 
Chicago, IL, USA). Differences in the pharmacokinetic (PK) parameters of rocuronium 
related to systemic exposure (i.e., Cmax, AUClast, and AUCinf) according to the 
sugammadex dose groups were compared using the Kruskal−Wallis test, followed 
by the nonparametric post-hoc evaluation using the Dwass, Steel, Critchlow-Fligner 
procedure implemented in the SAS software (version 9.3; SAS Institute, Inc., Cary, 
NC, USA).