A randomized Phase I pharmacokinetic trial comparing the potential biosimilar trastuzumab (SIBP-01) with the reference product (Herceptin®) in healthy Chinese male volunteers

ABSTRACT

Objectives

This study aimed to evaluate the bioequivalence, safety, tolerability and immunogenicity of the biosimilar trastuzumab (SIBP-01) compared to Herceptin®.

Methods

In this Phase I randomized double-blind parallel-group trial, 100 healthy male volunteers were randomized in a1:1 ratio to receive a single 6 mg•kg–1 intravenous dose of SIBP-01 or Herceptin®. Serum concentrationswere analyzed using a validated ELISA.

Results

The two groups had similar baseline characteristics. The geometric mean ratios (90% CI) of C_max, AUC_0-t and AUC_inf between the trial group and the reference group were 93.55%-104.27%, 91.98%-102.35% and 91.88%-102.34%, respectively; the geometric mean ratios (90% CI) of AUC_0-t and AUC_inf in the sensitivity analysis were 92.29%-102.63% and 91.81%-102.16%, respectively. These values were within the prespecified equivalence margins, establishing the bioequivalence of SIBP-1 and Herceptin®. AEs were similar across all subjects in the SIBP-01 and Herceptin® arms, with treatment-related AEs reported by 72.00% and 80.00%, respectively. In each group, there was one AE that caused a subject to discontinue the study.

Expert opinion

Trastuzumab (Herceptin®) is significantly more effective than chemotherapy in reducing exacerbations and tumor cell growth, and its adverse events are far lower than chemotherapy. Herceptin®is very expensive for most patients in China. The protein molecular primary structure of the biosimilar trastuzumab (SIBP-01) is consistent with Herceptin®, with highly similar high level structure, biologocal activity and purity.But there are few studies comparing the bioequivalence of SIBP-01 and Herceptin® in healthy subjects and cancer patients 2.

Conclusions

This study showed the PK similarity of SIBP-01 to Herceptin®. SIBP-01 was safe and well tolerated in healthy male volunteers, with no significant differences from the reference drug in safety or immunogenicity 4.

KEYWORDS:

• Trastuzumab
• SIBP-01
• bioequivalence
• pharmacokinetics
• phase I
• safety

1. Introduction

Trastuzumab (Herceptin®) is a humanized monoclonal antibody that can target HER-2 extracellular domain IV, block the expression of the HER-2 gene, and significantly improve the prognosis of HER-2-positive breast cancer patients [1]. Furthermore, trastuzumab, as a targeted drug, has been shown to be safer and more effective than conventional chemotherapy in the clinical treatment of diseases, and trastuzumab could be effective in more than 10% of patients with high expression of HER-2 who fail to respond to chemotherapy. Therefore, trastuzumab can be used in a single-drug regimen to treat metastatic breast cancer, even though patients have undergone one or more chemotherapy regimens unsuccessfully. Moreover, trastuzumab can be used with taxanes and other anticancer drugs to treat metastatic breast and gastric cancers and improve the survival rate and treatment response of HER-2-positive metastatic breast cancer and gastric cancer. Although biological products play an important role in the treatment of many serious and chronic diseases, the high costs often limit their use in patients, especially in developing countries [5]. There is a growing demand for biosimilars that are equally effective and safe but less expensive. Biosimilars are biological products that are highly similar to approved biological drugs and have no clinically significant differences in safety, quality, structure, or efficiency [6,7]. However, due to the structural complexity of biomacromolecules, they differ from traditional small-molecule drugs in their characteristics and are unlikely to be identical in structure to the reference drugs. As a result, the quality, safety, and efficacy of biosimilars may vary greatly. Many cases of cancer are complicated with heart disease. Antitumor drugs can cause toxicity to the heart, which is mainly manifested in the prolongation of the QT interval, leading to torsade de pointes. Electrocardiogram (ECG) changes in subjects are an important observation index that can be used to comprehensively evaluate the safety of antitumor drugs, detect cardiac toxicity, and provide a reference for similar anticancer drugs in the future. The U.S. Food and Drug Administration (FDA) guidelines recommend that a step-by-step approach be used to establish structural and functional similarity between biosimilars and reference or innovative products, including those developed from monoclonal antibodies [8,9]. The first step is usually to assess physical, chemical, and biological properties; the second step is to demonstrate the pharmacological equivalence between biosimilars and reference drugs; and the final step is to confirm that the biosimilars are as clinically effective and safe as the original drug [10]. SIBP-01 belongs to the second category of registered classification biological products. Its protein molecular primary structure is consistent with the original research drug, and its high-level structure, biological activity, and purity are highly similar to the original research drug [11]. This paper provides data from a Phase I clinical PK trial of pharmacokinetics in healthy male subjects to test the PK equivalence of SIBP-01 and Herceptin® 12.

2. Patients and methods

2.1. Study design

This randomized double-blind parallel-group trial was approved by the Clinical Medical Research and Ethics Committee of the First Affiliated Hospital of Bengbu Medical University. The ethical approval process of this study meets the requirements of Good Clinical Practice (GCP), the Declaration of Helsinki, and relevant domestic laws and regulations. All subjects provided written informed consent forms before initiation of any study-related procedure. The trial has been submitted to www.chinadrugtrials.org.cn with the identification code CTR20182452 13.

According to references, the inter-individual variation coefficient of the primary PK parameters of trastuzumab in healthy male subjects is about 13.7%～23.1%. The primary indicator of the equivalence evaluation is AUC_0-t in this parallel-group trial. The equivalence acceptance interval of the geometric mean ratio between the two drugs is 80.00～125.00%. When choosing 90% power and the significance level of bilateral 0.05, assuming that the theoretical ratio of AUC_0-t was 0.95 and the variation coefficient was 30% (taking into account the previous pharmacokinetic data without test drug), the calculated sample size was 38 cases in each group. Considering the dropout rate of about 20% and the possible loss of visits, the final sample size was determined as 50 cases in each group, a total of 100 cases.

One hundred healthy subjects were selected and randomly assigned to the trial drug group (SIBP-01) and the reference drug group (Herceptin®) at a ratio of 1:1. The envelope random method was used in randomization. Subjects were admitted to the Clinical Research Center 1 day before the drug administration. Baseline data, such as vital sign, physical examination, and laboratory examination data were collected. The dosage was calculated from the baseline body weight.

After a 10-h overnight fast, all subjects completed PK and immunogenic blood sampling, 12-lead ECG, vital sign measurements, oral administration of 4 mg chlorpheniramine with 50 ml of warm water and intravenous injection of 5 mg of dexamethasone diluted with 2 or 4 ml of 0.9% sodium chloride within 30 minutes before infusion. The trial drug and the reference drug groups were given 6 mg/kg of the study drug, and intravenous infusion was completed in 90 minutes. Water was not allowed from 1 h before infusion to 1 h after infusion, excluding 50 ml of water for oral chlorpheniramine. Standard meals were provided by the Research Center 1 h after infusion. In addition, the subjects were forbidden to enter or leave the ward at will, to bring their own food, smoke, drink, exercise, or engage in strenuous activities during the observation period.

PK blood samples were collected at the following time points: prior to dose administration (within 1.0 h); 0.5, 1.0, and 1.5 hours after the start of dose infusion (immediately after completion of infusion); and 1.0, 4.0, 8.0, 12, 24, 72, 120, 168, 240, 336, 504, 672, and 840 hours after the dose. Blood samples to test for immunogenicity (antidrug antibody (ADA)/neutralizing antibody (NAb)) were collected at the following time points: prior to dose administration (within 1.0 hours) and 168, 336, 504, and 840 hours after the dose.

Approximately 2.5 ml of venous blood was collected and centrifuged at 2–8°C for 10–15 min with 1500–2000 g centrifugal force. After the preparation of serum samples, they were stored vertically at a temperature range of −60–90 °C until the plasma concentrations of the drug and reference drug were measured quantitatively by enzyme-linked immunosorbent assay (ELISA).

2.2. Study participates

Healthy adult male volunteers who met the following criteria were included in this study: age between 18 and 55; body mass index (BMI) of 19.0 to 26.0 kg.m⁻²; weight of 50.0 to 85 kg; and agreement to voluntarily take effective contraceptive measures during the study period and within 6 months after the infusion of the study drug. In addition, physical examination, vital signs, chest X-ray examination, abdominal B-mode ultrasonic examination, 12-lead ECG, and laboratory tests were required to be within the normal range or considered clinically nonsignificant by the investigator.

Participants were excluded if they had a history of chronic or serious diseases, such as those associated with the cardiovascular, liver, kidney, respiratory, blood and lymph, endocrine, immune, mental, nervous, and gastrointestinal systems; had major surgery within 2 months or were expected to undergo major surgery during the study period or within 2 months after the end of the study; had a history of blood donation (>400 ml) within 3 months prior to screening; had received any other research drug treatment or participated in another intervention clinical trial; had used any drug in the past 2 weeks; or tested positive for alcohol and contraband drugs.

2.3. Study outcome

The area under the serum concentration–time curve (area under the curve, AUC) from the time of dosing to the time of last quantifiable concentration (AUC_0-t) should be replaced with AUC_0-t was the primary indicator used to evaluate the most important PK bioequivalence between SIBP-01 and Herceptin®. Other important factors included the AUC from time zero extrapolated to infinity (AUC_inf), the maximum observed serum concentration (C_max), the time to C_max (T_max), volume of distribution (VD), elimination rate constant (λz), terminal half-life (T_1/2), drug clearance (CL), and mean residence time (MRT), as well as evaluation of safety, tolerability, and immunogenicity. All AEs that occurred during the study were recorded, regardless of etiology or seriousness. The safety endpoints of the trial were to assess the incidence of reported AEs and to detect changes in vital signs, clinical laboratory tests, and ECG.

2.4. Statistical analysis

PK parameters were calculated by noncompartmental techniques using Phoenix® WinNonlin®, version 7.0 (Pharsight Corporation, California, USA), and the actual blood collection time was used to calculate all the blood collection points when PK parameters were calculated. The calculated PK parameters included C_max, T_max, AUC_0-t, AUC_inf, T_1/2, λ_z, VD, and CL. First, the PK parameters were descriptively analyzed, and the equivalence of C_max, AUC_0-t and AUC_inf was then evaluated, among which AUC_0-t was the main evaluation index. In the evaluation of equivalence, the natural logarithm of the PK parameter was first assessed, and the difference value and 90% confidence interval (90% CI) of the difference value between the test drug and the control drug were calculated by the t-test method. The geometric mean ratio and the 90% CI of the ratio were obtained by taking the opposition number. If the 90% CI of the AUC_0-t geometric mean ratio was completely within the range of 80.00–125.00%, bioequivalence was established. Other PK parameters, safety/tolerability, vital signs, physical examination, laboratory tests, 12-lead ECG, chest X-ray, abdominal B-scan ultrasonography, and echocardiography were used to analyze the observed values and relative baseline changes by descriptive statistical methods. Continuous variables were tested for normality using the Kolmogorov–Smirnov test. Normally distributed variables are expressed as the mean ± standard deviation (mean ± SD), while nonnormally distributed variables are shown as the median (M) and interquartile range (IQR). Categorical variables are expressed as absolute numbers and percentages (%). Differences in continuous variables between groups were assessed by Student’s t test (normally distributed) or Mann–Whitney U test (nonnormally distributed). Differences in categorical variable distributions between groups were assessed by the χ² test or Fisher’s exact test as appropriate.

3. Results

3.1. Participants’ disposition and baseline characteristics

A total of 352 volunteers were screened, and 100 healthy eligible participants were enrolled and randomized. The baseline characteristics of the subjects were comparable across treatment groups (Table 1). Two participants in the SIBP-01 group and one participant in the Herceptin® group were lost to follow-up. A subject with random number 048 (reference group) withdrew from the trial after the D10 visit due to herpes zoster, which might be related to the study drug. A subject with random number 098 (trial group) had infusion reaction during the infusion of study drug during D0 visit, and the trial was terminated in advance. A subject with random number 067 (trial group) suffered from diarrhea. The subject took belladonna sulfamethazine without informing the researchers, and withdrew from the trial in advance after the D28 visit.

Table 1. Summary of the baseline characteristics of the two groups

Indicators	Trial Group (n = 50)	Reference Group (n = 50)	P value
Gender, n (%)			NA
Male	50 (100.00)	50 (100.00)
Female	0	0
Age (year)	29.67 ± 5.81	30.18 ± 8.02	0.717
Height (cm)	170.30 ± 5.88	170.51 ± 5.81	0.858
Weight (kg)	64.40 ± 6.53	65.70 ± 6.45	0.319
BMI (kg.m^−2)	22.18 ± 1.71	22.59 ± 1.68	0.229

BMI, body mass index; NA, Not applicable

3.2. Pharmacokinetics

After a single intravenous injection, the trial and reference drugs had similar mean serum concentration-time profiles (Figure 1).

Figure 1. Mean serum concentration–time profiles of SIBP-01 and Herceptin® over the course of the study

The geometric mean ratios (90% CI) of C_max, AUC_0-t, and AUC_inf between the trial group and the reference group were 93.55%-104.27%, 91.98%-102.35%, and 91.88%-102.34%, respectively, within the equivalent range of 80.00%-125.00%. Thus, the bioequivalence was confirmed (Table 2). The geometric mean ratios (90% CI) of AUC_0-t and AUC_inf as the primary pharmacokinetics parameters for sensitivity analysis were 92.29%-102.63% and 91.81%—102.16%, respectively, within the equivalence interval of 80.00–125.00%, further supporting the conclusion of bioequivalence (Table 3). In addition, all primary and secondary pharmacokinetic parameters are shown in Table 4.

Table 2. Main analysis results of bioequivalence evaluation

PK parameter	N	Geometric mean and ratio			Individual variation among subjects%CV	90% CI^a	Grasp degree %
		Trial group (T)	Reference group (R)	(T/R) %
Cmax (μg/mL)	49/50	119.60	121.10	98.77	16.35	93.55～104.27	>0.9999
AUC0-t (μg·h/mL)	49/49	17,343.29	17,875.27	97.02	16.02	91.98～102.35	>0.9999
AUCinf (μg·h/mL)	49/49	17,467.89	18,013.66	96.97	16.18	91.88～102.34	>0.9999
Tmax(h)	49/50	2.08	2.09	99.55	46.18	85.96～115.28	>0.9999
T1/2 (h)	49/49	109.96	108.63	101.22	19.69	94.81～108.07	>0.9999
λz (1/h)	49/49	0.0063	0.0064	98.79	19.69	92.53～105.47	>0.9999

C_max, maximum drug concentration; AUC_0-t, area under the serum concentration-time curve from the time of dosing to the time of last quantifiable concentration; AUC_inf, AUC from time 0 extrapolated to infinity; CI, confidence interval; T_max, the time to C_max; T_1/2, terminal half-life; λz, elimination rate constant

is the 90% CI for the geometric mean ratio of T/R

Table 3. Sensitivity analysis of primary PK parameters between trial and reference products (PK population)

PK parameter	N	Geometric mean and ratio			Individual variation among subjects %CV	90% CI^a	Grasp degree %
		Trial Group (T)	Reference Group (R)	(T/R) %
AUC0-t (μg·h/mL)	49/50^b	17,343.29	17,820.67	97.32	16.01	92.29～102.63	>0.9999
AUCinf (μg·h/mL)	49/50^b	17,467.89	18,036.07	96.85	16.10	91.81～102.16	>0.9999

AUC_0-t, area under the serum concentration-time curve from the time of dosing to the time of last quantifiable concentration; AUC_inf, AUC from time 0 extrapolated to infinity; CI, confidence interval.

^ais the 90% CI for the geometric mean ratio of T/R

^bOn the basis of the main analysis of equivalence evaluation, the AUC_0-t and AUC_inf parameters of the excluded subject with random number 048 (reference group) were included in BES for sensitivity analysis.

Table 4. Mean ± SD pharmacokinetic parameter results

Parameter	Mean ± SD (%CV)
	Trial Group (n = 49)	Reference Group (n = 50)^b
Tmax (h)	1.58 (1.43, 9.53)	2.43 (1.40, 9.53)
Cmax (μg/mL)	121.86 ± 24.41	122.00 ± 15.04
AUC0-t (μg·h/mL)	17,570.91 ± 2850.55	18,086.18 ± 2831.33
AUCinf (μg·h/mLh)	17,700.96 ± 2894.91	18,230.86 ± 2885.97
T1/2 (h)	111.81 ± 19.72	110.75 ± 21.49
λz (1/h)	0.0064 ± 0.0013	0.0065 ± 0.0013

T_max, time at which the maximum serum concentration was observed; AUC_0-t, area under the serum concentration-time curve from the time of dosing to the time of last quantifiable concentration; AUC_inf, AUC from time 0 extrapolated to infinity; T_1/2, terminal half-life; λz, elimination rate constant.

^bIn the reference group, only T_max and C_max were calculated according to the data of 50 cases, and other parameters were calculated according to the data of 49 cases.

3.3. Safety

Among the 100 subjects who were administered the drugs, the 50 subjects in the trial drug group had an adverse event rate of 72.00%. One case had an adverse event that led to withdrawal from the study due to an ‘allergic rash.’ The researchers determined that the adverse event was most likely related to the study drug. Of the 50 participants in the reference group, 80.00% had adverse events, including 1 case with an adverse event that led to withdrawal from the study. The researchers determined that the adverse event might be related to the drug. According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, the incidence of Class II adverse events in the trial drug group was lower than that in the reference drug group (6% versus 18%). There were no Class III or higher adverse events in the two groups. The three most common types of adverse events in the trial drug group were upper respiratory tract infection, blood in urine and skin rash, with incidence rates of 22%, 18.00%, and 12.00%, respectively. In the reference group, the most common adverse event was elevated triglycerides (12.00%), followed by hematuria, a decrease in high-density lipoprotein (HDL) cholesterol and upper respiratory tract infection, all with an incidence of 10.00%. However, the differences were not statistically significant (all P > 0.05). In addition, the total number of cardiac adverse reactions was higher in the trial group compared with the reference group, but the difference was not statistically significant (Table 5).

Table 5. Comparison of adverse events between treatment groups

Adverse Event Type	Trial Group (n = 50)	Reference Group (n = 50)	Total (n = 100)	P value
Upper respiratory infection	11 (22.00)	5 (10.00)	16 (16.00)	0.102
Erythrocytes in urine	9 (18.00)	5 (10.00)	14 (14.00)	0.249
Rash	6 (12.00)	4 (8.00)	10 (10.00)	0.505
Elevated triglycerides	3 (6.00)	6 (12.00)	9 (9.00)	0.485
Urinary tract infection	1 (2.00)	0 (0.00)	1 (1.00)	1.000^#
Diarrhea	2 (4.00)	4 (8.00)	6 (6.00)	0.674
Headache	0 (0.00)	1 (2.00)	1 (1.00)	1.000^#
Dizzy	2 (4.00)	1 (2.00)	3 (3.00)	1.000
Epistaxis	3 (6.00)	1 (2.00)	4 (4.00)	0.610
Nausea	1 (2.00)	0	1 (1.00)	1.000^#
Heart disease
Abnormal ST segment	2 (4.00)	2 (4.00)	4 (4.00)	1.000
Abnormal T-wave	1 (2.00)	2 (4.00)	3 (3.00)	1.000
PR interval shortening	0	2 (4.00)	2 (2.00)	0.495^#
Increased heart rate	1 (2.00)	0	1 (1.00)	1.000^#
Sinus bradycardia	2 (4.00)	0	2 (2.00)	0.495^#
Supraventricular premature contraction	1 (2.00)	0	1 (1.00)	1.000^#
Heart palpitations	0	1 (2.00)	1 (1.00)	1.000^#
Cardiac valve insufficiency	5 (10.00)	0	5 (5.00)	0.066

^#: Fisher’s exact test

In this study, immunogenicity was detected within 60 minutes before administration and on days 7, 14, 21, and 35 after administration. Of the 50 subjects in the trial drug group, only 1 case (random number 011) was positive for ADA on day 35, but the corresponding NAb test result of the ADA-positive subjects was negative. The ADA test results of 50 subjects in the reference drug group were all negative at each test time point.

In conclusion, the safety and immunogenicity of SIBP-01 were similar to those of a single intravenous administration of Herceptin® in healthy volunteers 3.

4. Discussion

In this trial, the safety and immunogenicity of SIBP-01 and Herceptin® in PK were similar, which is in accordance with previous studies on trastuzumab. These data support the continued development of SIBP-01 as a potential drug similar to trastuzumab.

The trial on PK similarity comparison was a parallel-control study rather than a crossover study because, when Herceptin® is administered every 3 weeks, its half-life is 15.1–23.3 days in metastatic breast cancer (MBC), 17.5–26.6 days in early breast cancer (EBC), and 12.6–20.6 days in advanced gastric cancer (AGC); with a weekly prescription, the half-life of MBC is 17.2–20.4 days, and the half-life of EBC is 19.7–23.2 days [15]. According to the design principles for general bioequivalence studies, combined with the long half-life and immunogenicity of trastuzumab, this product is not suitable for a crossover design to evaluate its bioequivalence. Therefore, a randomized, double-blind, Herceptin®-referenced trial design is recommended.

In terms of a bioequivalence comparison between the two drugs, the three main PK parameters of AUC_inf, AUC_0-T and C_max are similar to those of Herceptin®. For these three PK parameters, the 90% CIs were included within a predefined standard equivalence range of 80.00–125.00%, which is similar to the range used in previous PK studies of trastuzumab biosimilars, and the end points of T_max and T_1/2 were also similar in the two groups. The PK profile of trastuzumab is characterized by dose-dependent exposure, and patients with higher baseline levels of HER-2 receptor antigen shedding or more metastatic sites tend to have higher clearance [16]. As with target-mediated patients, healthy subjects can provide the most homogeneous population and can better highlight the PK difference between the trial drug and the reference drug. Trastuzumab is a noncytotoxic drug, and it is acceptable to select healthy volunteers in a single PK comparative study. However, for healthy women, there has been no previous experience with trastuzumab PK. Therefore, in this study, only healthy male volunteers were selected.

Among the aspects of drug administration, dosage should be fully considered, and the dose that is most sensitive to the potential difference in PK between biosimilars and reference drugs should be chosen under the premise of protecting the interests of healthy subjects. The dose and sampling time chosen for this study was based on previous research conducted on trastuzumab [17]. The 6 mg/kg dose provided sufficient exposure for the study drug to allow an accurate assessment of PK in healthy subjects within a linear kinetic dose range. PK parameters, including C_max and AUC_inf, were similar to those reported in healthy male volunteers who received a single dose of 8 mg/kg trastuzumab [17,18].

In this trial, the three most common adverse events in the trial drug group were upper respiratory tract infection, erythrocytes in urine, and skin rash. In the reference group, the four most common adverse events were elevated triglycerides and erythrocytes in urine and decreased HDL cholesterol and upper respiratory tract infection. However, in previous clinical trials, the most common side effect of trastuzumab was headache, followed by back pain [19,20]. It was speculated that the differences in side effects may be because the primary structure of the SIBP-01 protein is the same as that of the original drug, but the higher structure, biological activity, and purity may be different from those of the original drug. Alternatively, the differences may be related to study populations, ethnicities, and sample sizes. Similar previous biological tests of trastuzumab have paid relatively little attention to the adverse cardiac reactions of this drug. Because most cancer patients have heart disease, this study focused on the cardiotoxicity of tumor drugs to provide an important index for evaluating the safety of such drugs. As shown in Table 5, abnormal ST segment, abnormal T wave, PR interval shortening, increased heart rate, sinus bradycardia, and supraventricular premature contraction were observed on ECG. Although there was no significant difference between the two groups, the incidence of total adverse events in the SIBP-01 group was higher than that in the Herceptin group in the detection of cardiac organ diseases, which may be associated with a potential risk of cardiac toxicity. Therefore, the Phase III trial should focus on monitoring cardiotoxicity.

Furthermore, for the comparison of immunogenicity between the two groups, only 1 case was positive for ADA but tested negative for NAb in the trial drug group, while all the subjects in the reference group were negative at each time point. The difference was not statistically significant. The low incidence of ADA observed in this study is consistent with previously reported data on trastuzumab [14,21,22]. These data indicate low immunogenicity of SIBP-01 and trastuzumab.

This study also has some limitations. First, given the number of subjects in each arm, this study could not conclude whether the observed numerical difference in rash in a relatively small study was the result of a random event associated with the evaluation of multiple adverse events. A follow-up study in healthy subjects need to be conducted to estimate the relative risk of rash of SIBP-01 in comparison to trastuzumab. Second, there was no prior experience of trastuzumab PK in healthy females. Thus, this trial was limited to healthy male volunteers. In addition, this Phase I trial suggested that trastuzumab SIBP-01 was well tolerated and safe. Findings from this study remain to be confirmed in pivotal Phase III trials, especially in breast cancer patients, and our hospital has carried out a Phase III study regarding SIBP-01.

5. Conclusions

Injectable SIBP-01 at 150 mg (10 mL) per bottle, produced by Shanghai Biological Products Research Institute Co., Ltd., is bioequivalent to injectable trastuzumab (Herceptin®; 440 mg (20 mL) per bottle; produced by Shanghai Roche Pharmaceutical Co., Ltd.). In healthy male volunteers, the safety and immunogenicity of SIBP-01 were similar to those of a single intravenous administration of Herceptin®.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Z. H., D.L., and W.H. contributed to the conception and design. Z.H., C.S. and Z.X. conducted the analysis and interpretation of the data and participated in the drafting of the paper. X.J., G.Q., F.L., and W.Y. contributed to the management of drug and biological sample disposition. Z.J. contributed to quality control throughout the study. S.R. contributed to the study organization and implementation. S.Z. and L.B. participated in the sample collection. L.Y. provided medical supervision. All authors were involved in revising the paper critically for intellectual content and the final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Additional information

Funding

This trial was sponsored by the Shanghai Institute of Biological Products Co. Ltd., and this study was funded by  Natural Science Foundation of Anhui Province (2008085QH401).