European Journal of Pharmaceutical Sciences 141 (2020) 105134

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European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Safety, tolerability, and pharmacokinetics of adamgammadex sodium, a T

novel agent to reverse the action of rocuronium and vecuronium, in healthy
volunteers
YingYing Jianga,b,1, YuJun Zhanga,b,c,1, ShunJu Xianga, WenLing Zhaoa,b,c, Jin Liua,b,c, ,
⁎

WenSheng Zhanga,b,c,
⁎

a
Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University,
Chengdu, Sichuan, China
b
National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
c
Sichuan Engineering Laboratory of Transformation Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

ARTICLE INFO ABSTRACT

Keywords: Neuromuscular blockers (NMBs) selectively block neuromuscular transmission at the N2-nicotinic receptor on
Neuromuscular block antagonists motor neurons to paralyze skeletal muscles, and are mainly used to facilitate tracheal intubation and surgical
phase I study procedures. Rapid reversal is necessary in clinical practice to avoid profound block and reduce recovery time.
dose escalation Adamgammadex sodium is a modified γ-cyclodextrin derivative consisting of a lipophilic core and a hydrophilic
pharmacokinetics
outer end that forms an inactive tight inclusion complex with free molecules of rocuronium and vecuronium. In
adamgammadex sodium
preclinical study, adamgammadex produced a concentration-dependent reversion effect of neuromuscular
blockade induced by rocuronium in beagle dogs. Furthermore, adamgammadex had a less potential side effects
than sugammadex and other clinical used neuromuscular block antagonists. In this study, the objective was to
assess the safety, tolerability, and pharmacokinetics of single intravenous injection of adamgammadex in healthy
volunteers. Approved by the China Food and Drug Administration, 52 healthy volunteers (half male and half
female) were enrolled in this single-center, randomized, double-blind placebo-controlled study. No serious ad-
verse effects were happened in this study. The overall frequency of adverse effects in adamgammadex was
similar for that in placebo, and there was no specific adverse effect in adamgammadex. All of the volunteers
bearing the adverse effects were recovered to normal without any treatment or intervention. In pharmacokinetic
study, the value of half-time, Tmax, and clearance were not changed significantly, and the Cmax and AUC0–∞
increased with a similar ratio of the escalating doses. For dose proportionality analysis of adamgammadex, the
estimate of slope was close to 1, and it was not significantly different from 1 after doses (AUC0-∞, 0.9965
[90%CI, 0.9468, 1.046]; Cmax, 0.9462 [90%CI, 0.8800, 1.012]). Therefore, adamgammadex exposure in plasma
increased in a dose- proportional manner. The urinary route is a significant excretory pathway for adamgam-
madex, and it is mostly completed at 8 h. All the results in this study showed that adamgammadex may be a
novel safe neuromuscular blockade reversal agent .

1. Introduction reduce recovery time. The traditional neuromuscular block antagonists

Neuromuscular blockers (NMBs) selectively block neuromuscular
transmission at the N2-nicotinic receptor on motor neurons to paralyze
skeletal muscles, and are mainly used to facilitate tracheal intubation
and surgical procedures (Murphy, 2018; Murphy et al., 2004). Rapid
reversal is necessary in clinical practice to avoid profound block and
neostigmine and edrophonium are anticholinesterase drugs, which in-
hibit cholinesterase to reduce the degradation of acetylcholine
(Singh and Sadiq, 2019). However, they may cause side effects such as
bradycardia, salivation, bronchospasm, and vomiting due to their ef-
fects on muscarinic acetylcholine receptors and nicotinic receptors in
other tissues. In order to avoid these, cholinergic receptor antagonists

Corresponding authors at: Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China
⁎

Hospital, Sichuan University, Chengdu, Sichuan, China

E-mail addresses: scujinliu@gmail.com (J. Liu), zhang_ws@scu.edu.cn (W. Zhang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.ejps.2019.105134
Received 27 July 2019; Received in revised form 14 October 2019; Accepted 29 October 2019
Available online 31 October 2019
0928-0987/ © 2019 Elsevier B.V. All rights reserved.
Y. Jiang, et al.
are usually administered in combination with atropine, but it them-
selves are also associated with side effects such as tachycardia, dry
mouth, and blurred vision. Meanwhile, traditional neuromuscular
blockade antagonists have a limited effect against profound block.
Sugammadex sodium (Bridion®, Merck & Co., Inc.) is approved to
reverse muscle relaxation by rocuronium bromide in more than 80
countries (Groudine et al., 2007; Sacan et al., 2007; Shields et al., 2006;
Sorgenfrei et al., 2006; Sparr et al., 2007; Suy et al., 2007;
Vanacker et al., 2007). However, it has been rejected three times by the
U.S. Food and Drug Administration (FDA) in 2008, 2013, and 2015, due
to its potential allergic reactions, and it also carries a risk of post-
operative bleeding. It was finally approved with a caution against hy-
persensitivity reactions and anaphylaxis (Baldo and McDonnell, 2014;
Takazawa et al., 2014; Tsur and Kalansky, 2014). Furthermore, su-
gammadex also increased the risk of postoperative bleeding
(Carron, 2015; Rahe-Meyer et al., 2014).
Adamgammadex sodium acts similarly to sugammadex, with pre-
clinical studies demonstrating similar efficacy and fewer potential side
effects (Chen et al., 2015; Qi et al., 2018). It consists of a modified γ-
cyclodextrin derivative with a lipophilic core and a hydrophilic outer
end that forms an inactive tight inclusion complex with free molecules
of rocuronium and vecuronium. In beagle dogs, adamgammadex pro-
duces a concentration-dependent reversion effect of neuromuscular
blockade induced by rocuronium. In zebrafish, it has been found to
modulate tryptase, suggesting a lower potential for causing hy-
persensitivity and anaphylaxis. Finally, it shows negligible detrimental
effects on cardiac function and does not pose a risk of bleeding.
Adamgammadex has been approved by the China FDA (approval
number, 2015L05410) for clinical trials in reversing the neuromuscular
blockade effect induced by rocuronium and vecuronium. In this study,
we aimed to assess the safety, tolerability, and pharmacokinetics of
single intravenous injection of adamgammadex sodium in healthy vo-
lunteers.
2. Materials and methods
2.1. Subject recruitment
Approved by the China FDA, fifty-two healthy volunteers (half male
and half female) were enrolled in this single-center, randomized,
double-blind, placebo-controlled study at West China Hospital, Sichuan
University, Chengdu, China (registration number,
ChiCTR1900024437). Only healthy young male and female subjects
aged 18–40 with body mass index (BMI) of 19–26 kg/m2 and weight of
50–90 kg for males and 45–85 kg for females were included. The sub-
jects with diagnosed digestive, urinary, cardiovascular, circulatory,
respiratory, neuropsychiatric, endocrine, or and metabolic diseases
were ineligible for enrollment. The subjects were also excluded if they
had congenital hemorrhagic diseases, coagulative dysfunction, history
of allergic reactions (e.g., food allergies, drug allergies, specific allergic
reactions, or asthma attacks), sensitivity to cyclodextrin or other drugs,
recent febrile disease (past 7 days), previous use of sugammadex, or
abnormalities in X-ray chest radiography, 12-lead electrocardiographic
(ECG), blood biochemistry, urine biochemistry, serum virology, or
blood clotting function tests
2.2. Treatment
Eligible subjects were randomized to receive placebo or adam-
gammadex (Table 1). Based on the previous preclinical pharmacolo-
gical and toxicological studies, the no-observed-adverse-effect level
(NOAEL) of adamgammadex after 15-days repeated i.v. administration
was 200 mg/kg in rats (transfer to human equivalent dose, 32.3 mg/kg)
and 450 mg/kg in beagle dogs (transfer to human equivalent dose,
250 mg/kg). The minimum dose in this phase I escalating-dose trial,
0.5 mg/kg, was set as one-sixth of the NOAEL dose in rats. Meanwhile,
2
European Journal of Pharmaceutical Sciences 141 (2020) 105134
Table 1
Number of subjects treated in each dose group.
Adamgammadex dose group (mg/kg)
0.5 2 4 8 16 24 32
No. of subjects receiving 2 6 6 6 6 6 6
active
No. of subjects receiving 2 2 2 2 2 2 2
placebo
Total subjects 4 8 8 8 8 8 8
the maximum tolerance dose (MTD) in rats was more than 3 g/kg. Due
to the linear relationship of pharmacokinetic features with the dosage
in rats and beagle dogs, we set the highest dose of adamgammadex at
32 mg/kg.
Based on this range, we tested seven escalating doses of 0.5, 2, 4, 8,
16, 24, and 32 mg/kg. Each subject remained in the clinical unit from
the day before receiving adamgammadex or placebo until the day after
dosing. Follow-up visits were made 4 and 8 days after dosing. Prior to
beginning administration, one catheter was inserted into the median
cubital veins of the left and right arms for drug administration and
blood sample collection, respectively. Subjects were administered
adamgammadex diluted with saline to 125 mg/mL or placebo (saline
only) i.v. at 1 mL/s. After administration, an interim safety report was
made depending on the common terminology criteria (CTCAE, version
4.03) for adverse events (AEs), including the results of all safety as-
sessments during that period. The intensity of AEs was classified into
five categories according to the CTCAE version 4.03: grade 1, mild
(asymptomatic or mild symptoms, intervention not indicated); grade 2,
moderate (minimal, local or noninvasive intervention indicated); grade
3, severe (medically significant but not immediately life-threatening);
grade 4, serious (life-threatening consequences, urgent intervention
indicated); and grade 5, death related to AEs. The last two were clas-
sified as serious AEs.
Groups were tested in succession with the lowest dose group tested
first. Subsequent groups receiving increased doses were tested only if
the agent was found to be safe and well-tolerated in the previous
groups. Testing was suspended when more than 50% of treated subjects
in a dose group showed drug-related AEs of level 2 or above.
2.3. Safety assessment
Physical examinations were performed at 24 h post-dose. Basic vital
signs including blood pressure, breathing rate, heart rate, and tem-
perature were measured prior to dosing and 2, 4, 8, 12, and 24 h after
dosing. Twelve-lead ECG was monitored continuously from 10 min pre-
dose to 40 min post-dose, and it were gathered at prior to dosing, 15 s,
2, 3, 4, 5, 6, 8, 10, 15, 25, 40 min, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after
dosing. Coagulative function was measured 30 min before dosing and
again at 3, 10, 25, and 40 min, and at 1, 3, and 24 h post-dose. These
examinations were repeated at follow-up visits. Signs of anaphylaxis
were noted at 24 h post-dose, including erythema, urticaria, angioe-
dema, hypotension, bronchospasm, and asthma (Brown, 2004). At 48 h
post-dose, we further evaluated hyperpyrexia, lymphadenectasis, er-
ythema, papules, pustules (acute generalized eruptive pustulosis),
blisters or blebs (epidermolysis bullosa), liver injury, eosinophilia, and
neutrophilia. Related clinical symptoms of anaphylaxis were evaluated
during the follow-up visit. Blood trypsin levels were tested in subjects
with anaphylaxis within 3 h of onset.
2.4. Pharmacokinetic study
Venous blood samples were collected at 0, 2, 3, 4, 5, 6, 8, 10, 15, 25,
and 40 min, and at 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after administration
to quantify the concentration of adamgammadex in plasma. Blood
samples were also collected at the same for subjects receiving the
Y. Jiang, et al. European Journal of Pharmaceutical Sciences 141 (2020) 105134

placebo. Blood samples (4 mL) were transferred to anticoagulant-coated Table 3

tubes and centrifuged at 1500–2000 g and 2–8 °C within 15 min to The summary of all adverse events (AEs) in this study.
obtain plasma, which was transferred into two sample tubes and stored Dose group Placebo Adamgammadex
at −70 °C. Urine samples were collected prior to dosing and at 0–2, No. of subjects No. of AEs No. of subjects No. of AEs
2–4, 4–6, 6–8, 8–10, 10–12, and 12–24 h post-dose. Timing and volume
0.5 mg/kg 2 (100%) 5 1 (50.0%) 1
of urine were recorded at each time point and two 1 mL samples were
2 mg/kg 1 (50.0%) 1 4 (66.7%) 7
retained and stored at −20 °C. 4 mg/kg 0 0 1 (16.7%) 2
Concentration of adamgammadex in plasma and urine were de- 8 mg/kg 1 (50.0%) 1 3 (50.0%) 5
termined at Q2 Solutions Co., Ltd. (Beijing, China) according to liquid 16 mg/kg 1 (50.0%) 1 2 (33.3%) 2
chromatography-mass spectrometry (LC/MS) methods developed and 24 mg/kg 1 (50.0%) 1 5 (83.3%) 9
32 mg/kg 2 (100%) 3 4 (66.7%) 6
validated by the China FDA (Pharmacopoeia, 2015) and the U.S. FDA
Total 8 (57.1%) 12 20 (52.6%) 32
(FDA, 2001; Viswanathan et al., 2007). The LC/MS system consisted of
an API 5500 mass spectrometer (AB Sciex) and Waters Acquity UPLC
system equipped with the Acquity UPLC BEH C18 Column (1.7 μm,
2.1 mm × 50 mm). Separation was carried out using 0.05% ammonium each group, the ratio of male and female was 1:1, mean age was
hydroxide in water as mobile solvent A and methanol/acetonitrile, the 24.2 ± 2.9 years old, mean body height was 1.64 ± 0.08 m, baseline
solvent B, at a volume ratio of 50:50, at an initial flow rate of 200 μL/ weight was 59.21 ± 9.52 kg, and BMI was 21.79 ± 2.00 kg/m2. Three
min at 40 °C with a TurboIonSpray™ in negative mode and selected subjects had a history of smoking and none had a history of alcohol
reaction monitoring (SRM) scanning. A selected reaction monitoring abuse, drug abuse, allergy, or blood donation within the previous 3
mode at transitions of m/z 613.3 → 128.0 for adamgammadex and m/z months.
327.0 → 157.0 for the internal standard (labetalol) was used for
quantification with negative electrospray ionization interface. 3.1. Safety

2.5. Data analysis
The pharmacokinetic analysis and inferential analysis of pharma-
cokinetic parameters were accomplished by IQVIA™ (Shanghai, China).
Pharmacokinetic parameters were calculated by non-compartmental
model using Phoenix WinNonlin® (version 6.4, NJ, USA). For the cal-
culation purpose, pre-dose samples that were below the lower limit of
quantitation (LLOQ) or missing were assigned a numerical value of
zero. Parameters of pharmacokinetic in this study were as follows: the
value of maximum concentration (Cmax) and the time to acquire (Tmax);
the elimination half-time (t1/2); area under curve (AUC) from zero to
the last time point (AUC0–t), from zero to 24 h post-dose (AUC0–24) and
from zero to infinity (AUC0–∞), clearance (CL), volume of distribution
(Vd), and apparent terminal rate constant (Kel). The following phar-
macokinetic parameters in urine were estimated: cumulative amount of
drug excreted in urine from zero to 24 h post-dose (Ae(0–24)), cumula-
tive fraction of dose excreted unchanged in urine from zero to 24 h post-
dose (fe(0–24)), and renal clearance (CLr = Ae(0–24)/AUC0–24). The dose
proportionality analysis was calculated according to the equation
below:
The linear model: log(Y ) = intercept + slope × log(dose)
Exponentiation of both sides:Y = exp(intercept) × doseslope
3. Results
Of the 65 subjects signed the informed consent, 38 received
adamgammadex and 14 received placebo. The number of subjects in
each dose group and their demographics and other baseline char-
acteristics are shown in Tables 1 and 2. There were no premature dis-
continuations from the study, and all subjects completed the trial. In
There were no serious AEs, and no subjects withdrew from the trial
due to AEs. Among those receiving adamgammadex, 20 subjects
(52.6%) experienced a total of 32 AEs (Table 3). In the placebo group,
eight subjects (57.1%) experienced a total of 12 AEs. Three cases of
clinical symptoms or disease were observed in those receiving adam-
gammadex (dizziness, cough, and upper respiratory infection), which
were judged by the investigator as non-related to the drug. Among
those receiving adamgammadex, clinical laboratory examination in-
dicated increased blood ketone bodies in 15.8% of subjects, increased
triglycerides in 7.9%, increased β2-microglobulin in 7.9%, decreased
fibrinogen in 5.3%, increased urinary glucose in 5.3%, increased ur-
inary ketone bodies in 5.3%, increased urobilinogen in 5.3%, and he-
maturia in 5.3%. In those receiving placebo, the incidence rate of ur-
inary ketone bodies increased in 28.6%, urinary glucose increased in
14.3%, triglycerides increased in 7.1%, thrombin time increased in
7.1%, fibrinogen decreased in 7.1%, activated partial thromboplastin
time increased in 7.1%, urinary ketone bodies increased in 7.1%, and
white blood cells were found in 7.1%.
A total of 11 AEs in eight subjects were judged as possibly related to
adamgammadex (Table 4). These included seven cases of increased
blood ketone bodies in (15.8% of subjects), two cases of increased ur-
inary glucose (5.3% of subjects), and two cases of increased urinary
ketone bodies (5.3% of subjects). Among those receiving placebo, eight
potentially related AEs occurred, including four cases of increased
blood ketone bodies (28.6% of subjects), two cases of increased urinary
glucose (14.3% of subjects), one case of increased urinary ketone bodies
(7.1% of subjects), and one case of prolonged thrombin time (7.1% of
subjects; Table 4).
Overall, adamgammadex-induced AEs had a lower incidence rate
than placebo, including increased blood ketone bodies (15.8% vs.
28.6%), increased urinary glucose (5.3% vs. 14.3%), and prolonged
thrombin time (0% vs.7.1%). There were no AEs specific to

Table 2
Characteristics of subjects (mean ± SD).
0.5 2 4 8 16 24 32
mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

Age, yr 27.0 ± 2.5 21.6 ± 1.5 23.1 ± 3.6 25.4 ± 3.9 24.9 ± 1.7 25.0 ± 1.5 23.9 ± 2.6
Sex, M&F 2&2 4&4 4&4 4&4 4&4 4&4 4&4
Height, cm 166 ± 3 164 ± 6 161 ± 8 165 ± 11 165 ± 10 166 ± 9 164 ± 9
Weight, kg 59.0 ± 5.9 57.0 ± 8.3 55.9 ± 10.8 59.4 ± 9.9 60.8 ± 13.1 61.6 ± 8.6 60.6 ± 9.4

3
Y. Jiang, et al. European Journal of Pharmaceutical Sciences 141 (2020) 105134

Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Outcome
Treatment

None
None
None
None
None
None
None
None
a
Intensity

I
I
I
I
I
I
I
I
Serum β-hydroxybutyrate ↑ (0.38 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.42 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.36 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.37 mmol/L, [0.02–0.27 mmol/L])

Urine ketone body ↑ (2.0 (1+) mmol/L, [-])
Urinary glucose ↑ (8.3 (2+) mmol/L, [-])

Urinary glucose ↑ (3.9 (1+) mmol/L, [-])

Adverse event (value, [normal range])

Thrombin time ↑ (23.5 s, [14 – 22 s])

Fig. 1. The mean plasma concentration-versus-time curves (A) and the cumu-
lative excretion in urine (B) in healthy volunteers receiving single doses of
adamgammadex sodium (2–32 mg/kg).
Placebo group

0.5 mg/kg
0.5 mg/kg
0.5 mg/kg
0.5 mg/kg

16 mg/kg
24 mg/kg
32 mg/kg
2 mg/kg

adamgammadex. All subjects experiencing AEs recovered without any

Dose

treatment or intervention. No changes in basic vital signs or clinically

meaningful ECG abnormalities were observed. Summarily, the fre-
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Outcome

quency and categories of AEs did not differ significantly among the
doses tested, nor from placebo. These findings indicate that adam-
gammadex was well tolerated.
Treatment

Reference to the common terminology criteria for adverse events (CTCAE, version 4.03).
Adverse events judged as possibly related to administration of adamgammadex and placebo.

3.2. Pharmacokinetics
None
None
None
None
None
None
None
None
None
None
None

Following a single intravenous injection of 2, 4, 8, 16, 24, or 32 mg/

a

kg adamgammadex, mean plasma concentrations declined rapidly, with

Intensity

t1/2 calculated as 1.6–2 h (Fig. 1A, Table 5). Plasma concentrations fell
below LLOQ after 10 h for the 2, 4, and 8 mg/kg dose groups and after
I
I
I
I
I
I
I
I
I
I
I

14 h for the 16, 24, and 32 mg/kg dose groups. Tmax was from 0.050 to
Serum β-hydroxybutyrate ↑ (0.35 mmol/L, [0.02–0.27 mmol/L])
Serum β-hydroxybutyrate ↑ (0.42 mmol/L, [0.02–0.27 mmol/L])
Serum β-hydroxybutyrate ↑ (0.50 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.38 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.35 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.45 mmol/L, [0.02–0.27 mmol/L])

Serum β-hydroxybutyrate ↑ (0.57 mmol/L, [0.02–0.27 mmol/L])

0.070 h (3–4 min), and the average CL ranged from 5.2 to 7.3 L/h.
Values of t1/2, Tmax, and CL were not significantly affected by increasing
dose. However, Cmax and AUC0–∞increased in a similar ratio over the
full range of doses tested. For dose proportionality analysis of adam-
gammadex (Fig. 2), the estimate of slope was close to 1, and it was not
Urine ketone body ↑ (1.0 (1+) mmol/L, [-])

Urine ketone body ↑ (1.0 (1+) mmol/L, [-])

significantly different from 1 after single doses of 2, 4, 8, 16, 24, and

Urinary glucose ↑ (3.9 (1+) mmol/L, [-])

Urinary glucose ↑ (17 (3+) mmol/L, [-])

32 mg/kg (AUC0–∞, 0.9965 [90%CI, 0.9468, 1.046]; Cmax, 0.9462

Adverse event (value, [normal range])

[90%CI, 0.8800, 1.012]). Therefore, adamgammadex exposure in

plasma increased in a dose-proportional manner.
The cumulative amount of adamgammadex excreted in the urine
increased with dose (Table 6). In different dose groups, the mean cu-
mulative fraction of adamgammadex ranged from approximately
73%–93% (Fig. 1B). Broadly, urinary excretion was a significant ex-
cretory pathway for adamgammadex, and was mostly complete at 8 h
after dosing.
Adamgammadex group

4. Discussion
16 mg/kg
16 mg/kg
24 mg/kg
24 mg/kg
24 mg/kg

Sugammadex was developed by modifying γ-cyclodextrin of the

2 mg/kg
4 mg/kg
4 mg/kg
8 mg/kg
8 mg/kg
8 mg/kg
Table 4

parent structure and adding mercaptopropionic sodium side chains

Dose

(Abad-Gurumeta et al., 2015), which reduce the “molecular binding

4
Y. Jiang, et al. European Journal of Pharmaceutical Sciences 141 (2020) 105134

Table 5
Pharmacokinetic parameters of adamgammadex sodium in plasma.
Parameter Geometric mean (GCV%)
2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg 32 mg/kg

AUC0–∞ (µg*h/mL) 15.24 (10.7) 41.39 (18.5) 77.29 (14.9) 143.2 (10.7) 215.8 (15.0) 251.1 (14.8)
AUC0–t (µg*h/mL) 15.03 (10.7) 40.96 (18.4) 76.42 (14.3) 142.5 (10.9) 215.3 (15.0) 249.8 (14.5)
AUC0–24 (µg*h/mL) 15.42 (11.5) 42.17 (18.7) 78.72 (15.3) 143.6 (10.9) 216.4 (15.1) 251.7 (14.9)
Cmax (µg/mL) 23.92 (16.3) 47.07 (19.3) 120.2 (17.6) 194.5 (29.2) 250.9 (17.7) 334.7 (24.6)
Tmax (h) [a] 0.050 (0.03–0.05) 0.070 (0.05–0.10) 0.050 (0.05–0.07) 0.070 (0.05–0.08) 0.070 (0.05–0.07) 0.070 (0.05–0.08)
t1/2 (h) 1.616 (11.3) 1.644 (4.5) [b] 1.685 (18.1) 1.963 (13.6) 1.755 (8.0) 1.898 (12.2)
CL (L/h) 7.042 (17.3) 5.223 (12.5) 5.647 (9.1) 6.338 (19.2) 6.416 (20.2) 7.298 (12.6)
Vd (L) 16.41 (25.5) 12.36 (17.2) 13.72 (19.2) 17.98 (28.2) 16.23 (18.1) 19.97 (9.6)

GCV% = percent coefficient of variation of geometric mean; AUC = area under the curve; t1/2 = half-time; CL = clearance; Vd = volume of distribution.
[a]
Presented as median (minimum–maximum).
[b]
n = 6. Subject 022 in the 4 mg/kg dose group had missing samples at 2, 3, 4 min. Except for t1/2, the rest of the PK parameters could not be reliably estimated
and therefore were excluded from summary statistics.

specificity” of sugammadex due to the absence of chiral carbons. With a
large number of such carboxyl groups, sugammadex may also capture
non-targeted substances, like intrinsic proteins, in vivo, which may lead
to produce the potential risks of side effects. As mentioned above, su-
gammadex was proven that it increased the risk of allergic reactions
and postoperative bleeding (Baldo and McDonnell, 2014; Carron, 2015;
Rahe-Meyer et al., 2014; Takazawa et al., 2014; Tsur and
Kalansky, 2014). Strengthening the chirality of the cyclodextrin could
lead to improvement in the molecular binding specificity. Adamgam-
madex, developed by Hangzhou Adamerck Pharmlabs Inc., introduced
amino acid derivatives with chiral carbons to each sugar unit of γ-cy-
clodextrin, enhancing at least 20% of chiral carbon atoms and greatly
improving specificity. As the modified γ-cyclodextrin derivative,
adamgammadex is composed of a lipophilic core and a hydrophilic
periphery which forms an inactive and tight complex with free rocur-
onium or vecuronium molecules. Determined by the isothermal titra-
tion calorimetry, adamgammadex combined with rocuronium at an
equivalent molar ratio for reversing its neuromuscular blockade effect
(Chen et al., 2015). Furthermore, the potential side effects induced by
sugammadex such as sensitization, bleeding and HR (including ven-
tricular fibrillation, ventricular tachycardia, cardiac arrest, and brady-
cardia) were measured in the zebrafish and beagle dog models
(Qi et al., 2018). The results from the preclinical pharmacological and
toxicological studies demonstrated that adamgammadex had a similar
efficacy and fewer side effects than sugammadex. Therefore, the added
chiral carbon atoms in the γ-cyclodextrin increases the steric hindrance
of carboxyl groups which reduced the binding rate with non-targeted
molecules to decrease the potential risks of anaphylaxis and other side
effects.
In this clinical trial, we found no changes in basic vital signs or
clinically meaningful ECG abnormalities, and all AEs were mild.
Further, the frequency of AEs in adamgammadex was similar to that of
placebo, and there was no AEs specific to adamgammadex. All volun-
teers experiencing AEs without treatment or intervention. In contrast,
sugammadex is associated with side effects such as hypotension, dry
mouth, nausea, anaphylaxis, bleeding, and prolonged QT interval
(Fuchs-Buder et al., 2013; Gijsenbergh et al., 2005; Takazawa et al.,
2016). These side effects were not present in adamgammadex.
In preclinical pharmacokinetic studies (Chen et al., 2015; Qi et al.,
2018), no metabolites of adamgammadex have been identified in the
hepatocytes from various species, plasma, or urine. The main dis-
tribution and excretion of adamgammadex in rats occurs in the kidney,
where it is excreted without any biotransformation reactions. Measured
by the isothermal titration calorimetry, adamgammadex, similar to
sugammadex, combined with rocuronium at an equivalent molar ratio
for reversing its neuromuscular blockade effect. After a single injection
in healthy subjects, the half-time, clearance, renal clearance rate, ap-
parent volume of distribution, and mean residence time had minimal
changes. Compared with sugammadex (Gijsenbergh et al., 2005;
Sorgenfrei et al., 2006; Sparr et al., 2007; Staals et al., 2010), adam-
gammadex had a lower t1/2 value of 1.8 h and higher urinary excretion
ratio of 83%. With rapid clearance and non-biotransformation reac-
tions, adamgammadex yielded rapid urinary excretion of combined
rocuronium and fewer potential risks related to drug accumulation.
Notably, the required adamgammadex dose might be greater than su-
gammadex to generate equivalent effects. However, adamgammadex at
2, 8, and 32 mg/kg performed as well as sugammadex at 8 mg/kg in
reversing the effect of rocuronium in beagle dogs.
Adamgammadex is expected to avoid the side effects of su-
gammadex and provide an effective and safe option for clinical an-
esthesia. All results from animal experiments and the phase I clinical
trial demonstrate that adamgammadex can be expected to be a safer
relaxant binding agent.

Fig. 2. The dose-normalized individual value and geometric mean of AUC0–∞ (A) and Cmax (B) in healthy volunteers receiving single doses of adamgammadex
sodium (2–32 mg/kg).

5
Y. Jiang, et al.
Table 6
Pharmacokinetic parameters in urine (mean ± CV%).
2 4 8 16
mg/kg mg/kg mg/kg
Ae(0–24) (µg) 90,200 ± 6.2 161,900 ± 39.5 404,300 ± 21.9
fe(0–24) (%) 86.4 ± 7.5 73.3 ± 29.5 91.2 ± 9.9
CLr (L/h) 5.9 ± 13.9 3.8 ± 35.5[a] 5.2 ± 15.4
CV% = coefficient of variation; AUC = area under the curve; fe = fractional excretion occurs through the kidneys; CLr = renal clearance rate.
[a]
Missing the plasma sample at 2, 3, 4 min (subject 022), AUC0–24 for that subject was not reliably for calculating the CLr.
5. Conclusions
In this study, adamgammadex sodium for injection was safe and
well tolerated up to a dose of 32 mg/kg. No drug-related serious AEs
were found when administration to 38 healthy subjects, and the overall
frequency of AEs in adamgammadex was similar for that in placebo.
Pharmacokinetic variables remained unchanged regardless of the dose,
indicating a linear pharmacokinetic property of adamgammadex over
the dose range. Meanwhile, adamgammadex was primarily excreted by
the kidney. All the results in this study showed that adamgammadex
may be a novel safe neuromuscular blockade reversal agent.
CRediT authorship contribution statement
YingYing Jiang: Data curation, Formal analysis, Writing - original
draft. YuJun Zhang: Data curation, Formal analysis, Writing - original
draft. ShunJu Xiang: Conceptualization. WenLing Zhao: . Jin Liu:
Data curation, Writing - review & editing. WenSheng Zhang: Data
curation, Writing - review & editing.
Declaration of Competing Interest
None.
Funding
This work was supported by the National Major Scientific and
Technological Special Project (grant numbers 2012ZX09103-101-012,
2016ZX09101066), and the National Innovation Fund (grant number
12C26213302758).
Acknowledgments
We are grateful to all experts and staffs for their assistance in this
clinical study: Dr. Jia Miao from Safety Committee, West China
Hospital, Sichuan University; Dr. Ye Zhu, Dr. Jingyi Li, Dr. Lichuan
Yang, et al., Division of Phase I Clinical Studies and Pain Management,
West China Hospital, Sichuan University; Dr. Shuning Zhang, Huilan
Hu, Jiaqi Lu, Ying Gu, Jiao Wei, Yuan Tian, and Baochun Yu, Adamerck
team members. Special gratitude goes to all subjects in this clinical trial.
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