ANNALS OF MEDICINE

2021, VOL. 53, NO. 1, 375–383

https://doi.org/10.1080/07853890.2021.1887925

ORIGINAL ARTICLE

A randomized phase-I pharmacokinetic trial comparing the potential

biosimilar tocilizumab (QX003S) with the reference product (ActemraV) in
R

Chinese healthy subjects

Hong Zhanga, Xiaojiao Lia, Jingrui Liua, Cuiyun Lia, Min Wua, Xiaoxue Zhua, Jixuan Suna, Min Fangb and
Yanhua Dinga
a
Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China; bQyuns Therapeutic Co. Ltd., Taizhou City, Jiangsu
Province, China

ABSTRACT ARTICLE HISTORY

Purpose: QX003S is a biosimilar candidate for the reference tocilizumab, ActemraV R . We investi- Received 16 November 2020
gated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Revised 22 January 2021
Chinese male subjects. Accepted 3 February 2021
Design: A randomised, double-blind, two-arm, parallel study was performed to examine the bio-
KEYWORDS
equivalence of QX003S (8 mg/kg) with that of ActemraV R as a reference drug.
Tocilizumab; biosimilar;
Results: QX003S (N ¼ 40) and ActemraV R (N ¼ 40) groups exhibited similar PK properties. The
immunogenicity; pharmaco-
inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the kinetics; inter-subject
ratios for Cmax, AUC0–t andAUC0–1 in both groups were within the range of 80–125%. After variability
administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the
QX003S group and ActemraV R groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reac-

tions occurred in 100% and 97.6% subjects in the QX003S and ActemraV R groups, respectively.

The most common adverse reactions were decrease in fibrinogen level and neutrophil and
leukocyte counts.
Conclusion: The PK characteristics and immunogenicity exhibited by QX003S were similar to
that of the reference product, ActemraV R . The safety profile was similar in the two treatment

groups with mild-moderate adverse effects.

TRIAL REGISTRATION
The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.
html#CTR20190002)

KEY POINTS
 This was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.
 This phase-I randomized, controlled study compared pharmacokinetics, variability,immunoge-
nicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).
 The results demonstrate bioequivalence between BAT1806 and the reference products
(Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.

1. Introduction The US Food and Drug Administration (FDA), the

Biological products are large and complex molecules, European Medicines Agency (EMA), and the National
usually derived from living cells. Due to the molecular Medical Products Administration (NMPA) have empha-
complexity and multifaceted production process, the sized a step-by-step approach for the development of
characteristics of biosimilars differ from those of the biosimilars [1]. Biological functional similarity is
traditional small-molecule drugs [1–3]. Despite signifi- assessed in the first step, followed by the assessment
cant therapeutic advances, biologic therapies, such as of pharmacokinetic (PK) and pharmacodynamic (PD)
monoclonal antibodies, are expensive with limited glo- characteristics; finally, the clinical similarity (efficacy,
bal access [4]. safety, and immunogenicity) is assessed using the

CONTACT Yanhua Ding [email protected] Phase I Clinical Trial Unit, The First Hospital, Jilin University, Changchun 130021, China
Supplemental data for this article can be accessed here.
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
376 H. ZHANG ET AL.

same approved dose and pathway as the reference between 14 March 2019 and 18 September 2019
product [1–3]. (Chinese Clinical Trial Registry, Registration No.
Tocilizumab binds to soluble and membrane-bound CTR20190002). The study protocol was approved by
interleukin (IL)-6 receptors and through these recep- the ethics committee of the hospital. The study com-
tors inhibits IL-6-mediated signal transduction. IL-6 is a plied with the guidelines of the Declaration of Helsinki
multipotent pro-inflammatory cytokine produced by a and the International Conference on Harmonisation
variety of cell types, including T and B cells, lympho- (ICH) Good Clinical Practice (GCP). Written Informed
cytes, monocytes, and fibroblasts. Synovial cells and consent was obtained from all subjects prior to
endothelial cells also produce IL-6, which induces the their enrolment.
inflammatory process in the joints (e.g. rheumatoid This was a randomized, double-blind, single-dose,
arthritis) [5–6]. Tocilizumab is effective against two-arm, parallel comparison study to evaluate the PK,
rheumatoid arthritis, giant cell arteritis, and multi-joint safety, and immunogenicity of QX003S and Actemra@
juvenile idiopathic arthritis. In a previous study, tocili- in healthy Chinese male subjects. Overall, 86 eligible
zumab reduced the likelihood of progression to the subjects were randomly allocated in a 1:1 ratio to
composite outcome of mechanical ventilation or dea- receive a single intravenous drip of 8 mg/kg QX003S
thin hospitalised patients with Covid-19 pneumonia; or Actemra@. Subjects were stratified into two groups
however, it did not improve survival of these patients. based on body weight (50 to < 67.5 kg and  67.5 to
Tocilizumab is currently under investigation as a  85 kg). Individuals in each of the pre-specified
potential treatment for COVID-19, with initial contra- groups were equally assigned to the two treatment
dictory evidence [7]. groups through randomization (Figure 1).
Consequently, tocilizumab biosimilars have been Sentinel staggered administration was used in this
actively developed around the world, including in study. Subjects were administered the investigational
China. Tocilizumab biosimilars (QX003S) have the product (IP) in a staggered cohort: the first and
same primary structure, post-translational modification, second cohort consisted of two subjects and four sub-
biochemical characteristics, and biological functions as jects, respectively. For safety evaluation, each subject
the reference product, and in addition, these similar- was required to stay at the study centre for at least
ities have been tested in mice and monkeys (data not 96 h after the administration. Based on sentinel safety
published). All in vivo studies justify the clinical devel- results, the principal investigator determined whether
opment of QX003S. the subsequent subjects would be monitored in senti-
PK studies in humans are essential to demonstrate nel mode or in routine follow-up mode. All subjects
the bioequivalence of biological analogues and refer- were followed up for 57 days.
ence products [8]. Herein, we conducted a single-dose The main inclusion criteria were as follows: (1)
PK study in healthy Chinese male subjects to evaluate healthy men in the age group of 18–50 years; (2) body
the bioequivalence between QX003S and Actemra@ as mass index: 18.0–28.0 kg/m2; (3) body weight:
the reference product. Use of healthy subjects helps 55–85 kg; and (4) normal test outcomes or clinically
avoid the potential confounding influence of factors unremarkable results of routine blood and urine rou-
such as comorbid diseases and concomitant therapies. tine investigations including hepatic and renal func-
The therapeutic dose of the reference drug used in tion tests during enrolment.
previous studies is 4–8 mg/kg [9–10]. In this study, a The exclusion criteria were as follows: (1) history of
dose of 8 mg/kg was used, based on earlier clinical clinically significant diseases; (2) C-reactive protein
trial plans of the sponsor. (CRP) levels 1.5 times higher than the upper limit of
In this study, the PK profiles of the QX003S with the normal range; and (3) positive results of T-SPOTV R
Actemra@ were analysed and compared. In addition, assay or TB interferon-c-release assay.
the tolerability, safety, and immunogenicity of QX003S All subjects received a single intravenous infusion
were assessed. of the IP (8 mg/kg) administered over a period of
60 min (±6 min). All subjects were randomly allocated
2. Methods to one of the following two groups in a 1:1 ratio in
each of the pre-specified weight intervals: QX003S
2.1. Study design and subjects
(Jiangsu Quanxin Biomedicine Co. Ltd; Batch number:
This phase-I study was conducted at the Clinical F20180801); Actemra@ (Chugai Pharmaceutical
Research Centre of the First Hospital of Jilin University Company [Japan]; Batch number: B2063B15).
 ANNALS OF MEDICINE 377

Figure 1. Flow chart of the study.

Screening was performed 14 to 2 days prior to the 2.3. Immunogenicity evaluations

date of administration. All qualified subjects entered the
Blood samples collected at 1 h before and on 15, 29,
clinical research unit a day prior to the administration of
43, and 57 days after drug administration were ana-
biosimilars. Subjects were required to fast for at least 8 h
lysed for the presence of anti-drug antibodies (ADAs)
before administration and were randomly assigned to
using electrochemiluminescence immunoassay (ECLIA).
either the test drug (QX003S) or reference drug group.
Subjects who test ADA-positive, those who develop
antibody-related adverse reactions, or those with sig-
nificantly abnormal PK value are required to be further
2.2. PK evaluations examined for the presence of neutralising antibodies
(NAbs). NAb test was not performed in this study
Blood samples were collected for PK analysis at differ-
because the above conditions were not met.
ent time-points: 1 h before administration (before
administration) to 1344 h after the initial infusion (day
57). Serum tocilizumab levels were determined by 2.4. Safety evaluation
enzyme-linked immunosorbent assay (ELISA) at the Physical examination, assessment of vital signs, electro-
Junke Zhengyuan (Beijing) Pharmaceutical Research cardiogram, and routine laboratory investigations were
Co. Ltd. (Supplement material). PK parameters were performed to monitor adverse events (AEs) according to
determined by non-compartmental analysis model. the National Cancer Institute Common Terminology for
The concentration–time data included the maximum Adverse Events (CTCAE;V.4.03). Subjects who showed
observable serum concentration (Cmax), clearance (CL), AEs were monitored until they reached normal or
half-life (t1/2), the volume of distribution (Vz), and area acceptable stability (as assessed by the principal investi-
under the curve (AUC) from zero to the final quantifi- gator and sponsor) or were lost to follow up.
able concentration (AUC0–t) and to infinity (AUC0–1).
The actual sampling times were used for PK analyses.
An internally validated software system, Phoenix
2.5. Estimation of the sample size
WinNonLinV R v8.0 (Pharsight Corporation, Certara, L.P., According to the recent FDA guidelines, the geometric
Princeton, New Jersey, USA), was used to determine mean ratio (GMR) was set at 95% to achieve 90%
PK parameters. power (1  b) at a significant level (two-sided a ¼ 5%).
378 H. ZHANG ET AL.

Inter-subject variability (inter-CV) is expressed by the 3.2. PK evaluation

coefficient of variation (CV). NQuery 8.3.0.0 (Boston,
The mean serum concentration–time curve of tocilizu-
USA) software was used to determine the sample size
mab and its biosimilar decreased with multiphase
(initial: 68; inter-CV for tocilizumab: 24%) [9]. The final
mode. A rapid decline immediately after the infusion
sample size was 86, allowing for a 20% drop-out rate.
was followed by a slow elimination phase, and, subse-
quently, by a slightly faster elimination phase at low
2.6. Statistical analysis concentrations (Figure 2). The non-compartmental
analysis model showed slow clearance, longer t1/2, and
After logarithmic transformation of PK parameters
small Vz of tocilizumab and its biosimilar. The median
Cmax, AUC0–t, and AUC0–1, the least square method
Tmax values were equivalent between the two groups
was used for analysis of variance. Bioequivalence infer-
and these were achieved 1.8 h after the intraven-
ences were drawn if the 90% confidence intervals (CIs)
ous infusion.
were found to be within the range of 80–125%. PK
The mean value of t1/2 between the test drug and
analysis was performed using the PK analysis set. The
the reference drug was between 160.8155 and
safety analysis set included subjects who were admin-
159.9160 h, indicating comparability. The total clear-
istered the study drug. Descriptive statistical estimates
ance rate (CL) and Vz values were also similar in the
of PK parameters and demographic data were calcu-
two groups. The differences between the mean con-
lated. Between-group differences were assessed using
centration–time curve, mean Cmax, AUC0-t, AUC0-1
the Chi-squared test for categorical variables, t-test for
estimation, and inter-CVs were similar (p > .05); the
normally distributed continuous variables, and
coefficient of variation ranged from 14.95% to 18.78%
Wilcoxon rank test for non-normally distributed varia-
(Table 2, Figure 2).
bles. All statistical analyses were performed using SAS
The PK parameters were comparable in the QX003S
9.4 (SAS Institute Inc., Cary, NC, USA).
and Actemra@ groups. The ratio of geometric least-
squares means for the QX003S versus Actemra@ were
3. Results 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-1;the
90% CI was 0.9272–1.06. The 90% CIs of the Cmax,
3.1. Subjects
AUC0–t, and AUC0–1 were within the predefined bioe-
The assigned drugs were administered to 83 of the 86 quivalence limit, ranging from 80.00% to 125.00%. A
enrolled subjects and included in the safety analysis larger inter-CV indicated a broader 90% CI. The sample
(Figure 1). One additional subject was included in the size was re-estimated on the basis of the results of
QX003S group, whereas one subject was removed from bioequivalence analysis (GMR and inter-CV), which
the ActemraV R group due to weight stratification. decreased to a number less than the enrolment size
Therefore, the QX003S group comprised of 44 subjects. (Table 2).
Before dosing, two and one subjects in the QX003S
and ActemraV R groups, respectively, had hypertension
3.3. Immunogenicity evaluation
and fast pulse rate or polycardia; these subjects were
excluded from the study. Before dosing, two and one Before dosing, two and one subjects in the QX003S
subjects in the QX003S and ActemraV R groups, respect- and ActemraV R group respectively, were ADA positive.

ively, were ADA positive;these were excluded from the After dosing, 6 (14.3%) subjects in the QX003S group
study. The final per-protocol analysis population included and 14 (34.1%) subjects in the ActemraV R group tested

in the safety, PK, BE, and immunogenicity (ADA) analysis positive for ADA. The ADA-positive rates were found
set comprised of 83, 80, 80, and 83 subjects, respectively to increase over a period of time, especially by days
(Figure 1). The demographic and baseline characteristics 43 (1008 h) and 57 (1344 h). Nevertheless, the drug
of the per-protocol population and the two treatment concentration was less than the lower limit of quanti-
groups were comparable (p > .05, Table 1). tation (LLOQ) during that period. ADA-positivity rates

Table 1. Demographic and baseline characteristics.

　 QX003S group ActemraVR group Total
(n ¼ 44) (n ¼ 42) (n ¼ 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
 ANNALS OF MEDICINE 379

Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values
within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.

Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S ActemraVR Re-estimated
group (n ¼ 40) group (n ¼ 40) p Values GMR (90% CI) GMR (90% CI)a size
Tmax(h) 1.8 (1-4) 1.8 (1-4) >.05 　 　 　
Cmax (lg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
(15.39)
AUC0-t (hlg/mL) 27116.0941 ± 4466.9216
(16.47)
27446.4185 ± 4103.9469 .73 0.9859 (0.9311,1.0439) 0.9827 40
(14.95) (0.9197-1.0500)
AUC0-1 (hlg/mL) 28806.7645 ± 5411.8467
(18.78)
29039.7894 ± 4641.0883 .83 0.9878 0.9787 52
(15.98) (0.9272, (0.9098-1.0529)
1.0524)
t1/2 (h) 160.8155 ± 35.2772 159.9160 ± 29.0054 .90
(21.93) (18.13)
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 .26
(13.68)
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 .46 　 　 　
(18.33)
Median [min, max]; aQX003S/ ActemraV
R after excluding subject with ADA positive after dosing.

Table 3. Summary of immunogenicity (anti-drug antibody)

The serum concentration-time curves of QX003S
assessment (number [%] of subjects with positive antibodies). and Actemra@ for ADA-positive and ADA-negative
Time (day) QX003S group (n ¼ 42) ActemraV
R group (n ¼ 41) p Values subjects were found to be similar (Figure 2). Sensitivity
Pre-dose 2 (4.88) 1 (2.44) .57 analysis of bioequivalence was performed after
15 0 (0) 0 (0) NA exclusion of 20 subjects who tested positive for
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43 ADA. The 90% CIs for the comparisons of Cmax and
57 8 (19.51) 13 (31.71) .18 AUC were within the predefined range of bioequiva-
NA: Not applicable.
lence limits of 80.00%–125.00% (Table 2). Therefore,
overall, ADA-positivity rates were similar in the
were similar in the two groups at 15 to 29 days after
two groups.
drug administration (6.7–7.1%). However, at 43 and
57 days after drug administration, the positivity rates
in the QX003S group were relatively lower than those
3.4. Safety evaluation
in the Actemra@ group; however, the between-group
differences in this respect were not statistically signifi- No serious AEs (SAEs), deaths, or discontinuations due
cant at any of the time-points (p > .05, Table 3). to AEs were observed. In this study, 282 adverse
380 H. ZHANG ET AL.

Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
　 QX003S group (n ¼ 42) 　 R group (n ¼ 41)
ActemraV 　
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14

reactions occurred in 82 (98.8%) subjects. A total of There was no association between ADA develop-
134 adverse reactions in 42 (100%) subjects were ment and adverse reactions in this study. None of the
recorded in the QX003S group, while148 adverse reac- subjects developed clinically significant or serious
tions in 40 (97.6%) subjects were recorded in the hypersensitivity, anaphylaxis, or injection-site reaction
ActemraV R group. The incidence of adverse reactions after IP administration, except Subject no.105 of the
was comparable in the two groups (Table 4). The QX003S group who developed ecchymia and mild ten-
adverse reactions with an incidence greater than 5% derness at the injection site 48 h after administration;
in the QX003S and ActemraV R groups, respectively,
this subject showed spontaneous recovery on day 8
were as follows: decreased fibrinogen level (90.5% vs without any treatment. Subject no.001 of the
82.9%), decreased neutrophil count (71.4% vs 58.5%), ActemraV R group showed bruising at the injection site
decreased white blood cell (WBC) count (57.1% vs at 12 h after administration without any tenderness;
46.3%), increased bilirubin (14.3% vs 7.3%), and hyper- this subject also showed spontaneous recovery on day
triglyceridaemia (11.9% vs 17.1%). The severity of most 22 without any treatment. All adverse reactions were
adverse reactions was between grade I and II. The inci-
reported to the Institutional Review Board of The First
dence rates of elevated alanine aminotransferase and
Hospital of Jilin University.
elevated aspartate aminotransferase level in the
QX003S group were lower than those in the ActemraV R

group (0% vs. 12.2%, p ¼ 0.01; 0% vs. 9.8%, p ¼ 0.03); 4. Discussion

this indicated a lesser effect of QX003S on liver
This single-dose, phase-I study demonstrated the bioe-
enzyme levels than the reference product. The inci-
quivalence of QX003S and Actemra@ when adminis-
dence of other adverse reactions was comparable in
tered as intravenous infusion at a dose of 8 mg/kg.
the two groups (p > 0.05).
The results of ANOVA showed that the 90% CIs of the
A total of 20 (24.1%) subjects in the two groups
experienced 26 grade III–IV adverse reactions. Thirteen geometric mean ratios of Cmax and AUC in the two
(31.0%) subjects in the QX003S group developed 16 treatment groups ranged from 92.72%–106%, which
adverse reactions, and seven (17.1%) subjects in the was within the predefined bioequivalence intervals of
ActemraV R group developed 10 adverse reactions. The 80% to 125%. Other PK parameters of Tmax and t1=2
incidence in the QX003S vs ActemraV R groups was were also similar between the two treatment groups.
comparable: decreased neutrophil count (28.6% vs QX003S and Actemra@ showed a similar safety and
12.2%), decreased WBC count (7.1% vs 7.3%), immunogenicity profile. No serious AEs were reported;
decreased fibrinogen (2.4% vs 2.4%), and increased all adverse reactions were mild or moderate in sever-
alanine aminotransferase (0 vs 2.4%). All grade III–IV ity, and no local reactions were reported except in
adverse reactions recovered spontaneously without two subjects. This indicated that the two products
treatment. Very few Grade I-II adverse reactions were well tolerated in this population of healthy sub-
required drug therapy, such as cefuroxime axetil, levo- jects. The above results justify the use of the biosimi-
floxacin, and glycyrrhizin. lars in the next phase clinical studies [1–3].
 ANNALS OF MEDICINE 381

Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard
error of the mean.

The pharmacokinetic behaviour of tocilizumab is dif- drug antibodies [9,13]. Similarly, ADA had no effect on
ferent from the small-molecule pharmacokinetic behav- drug concentration or bioequivalence results in this
iour in that it has limited vascular permeability, study (Figure 2, Table 2). In population PK analysis,
neonatal Fc receptor circulation, and more frequent body weight was identified as a significant covariate
receptor-mediated nonlinearity. Its distribution and impacting the pharmacokinetics of tocilizumab. When
clearance (CL) are consistent with target-mediated drug administered intravenously on mg/kg basis, individuals
disposition (TMDD) [11]. On average, Cmax of tocilizu- with body weight 100 kg are predicted to have
mab decreased approximately 55% in the first 96 h. higher exposures than individuals with body weight
Subsequently, a slow elimination phase was observed <100 kg. Therefore, weight stratification was adopted
between 96 and 336 h, followed by a relatively fast in this study to reduce variation of parameters,
elimination between 336 and 672 h (Figure 2). In this although the weight of subjects in this study was
study, QX003S at a dose of 8 mg/kg [mean weight of <100 kg. The inter-CV of tocilizumab was small (less
the subjects: 67.45 kg, dosage: 539.6 mg (4  67.45)] than 18.7867%); therefore, the sample size in future
showed a lower clearance and displayed a longer t1/2 studies can be reduced to 52 subjects (26 subjects per
(160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche arm) [14].
Products Limited, Welwyn Garden City, UK), more Notably, the incidence of adverse reactions in the
exposure (AUC ratio of QX003S vs tocilizumab 162 mg QX003S group was similar to that in the Actemra@
equal to 6.39) than dose ratio (539.6:162 ¼ 3.33), similar group (100% vs 97.6%); most of these were resolved
Tmax and dose ratio of Cmax with tocilizumab 162 mg, at the final visit in this study. The most common
which have been evaluated in other phase-I studies in adverse reactions (incidence of at least 5%) are
healthy subjects (Supplement Table 1) [12]. reported in the label, including upper respiratory tract
Population pharmacokinetic analyses in any patient infections, nasopharyngitis, headache, hypertension,
population tested so far indicate no relationship increased ALT level, and injection site reactions [9]. In
between apparent clearance and the presence of anti- healthy subjects who were administered ACTEMRA in
382 H. ZHANG ET AL.

doses of 2–28 mg/kg intravenously and 81–162 mg biosimilar showed a nearly similar ADA profile and a
subcutaneously, the absolute neutrophil counts comparable safety profile versus the reference drug.
decreased to the nadir 3 to 5 days following adminis- The inter-CV of tocilizumab was low among Chinese
tration. Thereafter, the neutrophil counts recovered subjects. These data support the clinical development
towards baseline in a dose-dependent manner over a of QX003S as a tocilizumab biosimilar.
period of 9–17 days [12]. Patients with rheumatoid
arthritis and GCA exhibited a similar pattern of abso-
Acknowledgements
lute neutrophil counts following the administration of
ACTEMRA [9,15]. Similar to previous reports, the inci- The authors thank the staff of the Phase I Clinical Research
dence of decreased neutrophil counts and decreased Centre, The First Hospital of Jilin University, Jilin, China for
data collection in the study.
white blood cell counts was indeed very high.
Neutrophil counts decreased on day 2 to 5; the mean
neutrophil count reached nadir on day 2 in both Disclosure statement
groups. The mean values returned to baseline by day All data related to this study were interpreted by the trial
57 without any treatment (Figure 3). As described by staff with complete independence from the sponsor. Min
Nishimoto et al. [16], when tocilizumab concentration Fang is employee of the sponsor team. The authors have no
is maintained above 1 mg/mL, SIL-6R is saturated by other relevant affiliations or financial involvement with any
tocilizumab leading to complete inhibition of the IL-6 organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
signal; this may affect the distribution of blood cells
manuscript apart from those disclosed.
such as neutrophils and leukocytes. However, these
cell counts quickly return to baseline with the drop in
the drug concentration. Funding
In clinical studies, RA patients were treated with This study was fully funded by the Jiangsu Quanxin
4–8 mg/kg intravenous doses or the 162 mg weekly Biomedicine Co. Ltd.
and every other weekly subcutaneous doses of
ACTEMRA; the levels of CRP decreased to within the
normal range along with changes in the pharmacody-
Data availability statement
namic parameters (i.e. decrease in rheumatoid factor,
erythrocyte sedimentation rate (ESR), serum amyloid The data that support the findings of this study are available
on request from the corresponding author, YHD. The data
A, fibrinogen; and increase in haemoglobin) [9]. In the
are not publicly available due to their containing informa-
present study, fibrinogen level decreased in tion that could compromise the privacy of research
82.9–90.5% subjects and the mean fibrinogen level participants.
reached the nadir on day 15 to 29 in the QX003S and
ActemraV R groups; these changes are similar to the

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