Abstract
CT‐P13, a biosimilar of infliximab, is used to treat inflammatory diseases that arise from immune system complications, resulting in excessive and persistent inflammation. The subcutaneous (SC) formulation of CT‐P13 overcomes the drawback of prolonged administration associated with the intravenous (IV) infliximab biosimilar, necessitating autoinjector (AI) administration. This randomized, open‐label, two‐arm, parallel‐group, single‐dose clinical pharmacology study aimed to evaluate the pharmacokinetics (PK) and safety of CT‐P13 SC administration via AI compared with the existing pre‐filled syringe (PFS) method. A total of 147 healthy participants were randomized into two groups, of which 139 completed the study. Blood samples were collected from before CT‐P13 SC administration to 2016 h after the start of the administration. Serum concentrations were analyzed using the Meso Scale Discovery electrochemiluminescence method. Geometric mean ratios (90% confidence interval) of the AUCinf (areas under the concentration–time curve from zero to infinity) and C max (The maximum serum concentration) for CT‐P13 SC AI versus CT‐P13 SC PFS groups, were 94.15% (85.02%–104.26%), 92.48% (84.66%–101.01%), respectively. CT‐P13 SC AI and CT‐P13 SC PFS achieved comparable PK because the 90% CI was within the predefined equivalence margin. At the end of the study, immunogenicity results revealed that 70 (97.22%) and 73 (98.65%) participants tested positive for anti‐drug antibody (ADA) in the CT‐P13 SC AI and CT‐P13 SC PFS groups, respectively. They were tested positive for neutralizing antibodies. No other significant safety differences were observed between the treatment groups. In conclusion, both administrations demonstrated PK equivalence and were both safe and well‐tolerated.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Infliximab is administered via intravenous and subcutaneous (SC) injections, which offers advantages in terms of cost, convenience, and patient preference when used with an autoinjector (AI). Therefore, the development of an SC formulation of infliximab using AIs is necessary to enhance patient experience and treatment efficacy.
WHAT QUESTION DID THIS STUDY ADDRESS?
This study evaluated the pharmacokinetics (PK) and safety of infliximab 120 mg/mL administered via an AI compared with those of a pre‐filled syringe (PFS) formulation to assess their bioequivalence.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The SC injection of infliximab 120 mg/mL administered via an AI demonstrated PK equivalence with the PFS treatment method in healthy volunteers.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The SC injection of infliximab 120 mg/mL via an AI was shown to be comparable to the PFS formulation, suggesting that an AI could serve as a viable alternative from the perspectives of the cost and convenience for patients. These findings could provide an important reference for the development of injection methods for other biological agents.
INTRODUCTION
Autoimmune diseases occur when the immune system attacks healthy tissues, which affects 3%–5% of the general population, ranging from teenagers to octogenarians. 1 , 2 These lifelong conditions can cause discomfort in daily activities and decrease the quality of life, posing significant challenges if they recur in daily life. 3
Infliximab, a tumor necrosis factor (TNF)‐targeting biological agent, was the first monoclonal TNF antibody introduced for human therapy. It is a recombinant deoxyribonucleic acid (DNA)‐derived chimeric human‐mouse immunoglobulin G monoclonal antibody that blocks the TNF signaling. 4 Infliximab promotes the lysis of cell lines expressing TNF‐α through complement and antibody‐dependent cellular cytotoxicity, reducing inflammation in tissues. It was developed for both intravenous (IV) and subcutaneous (SC) injections. 5 , 6 CT‐P13 IV is a biosimilar to both the US‐licensed Remicade and EU‐approved Remicade, with an identical primary sequence to each. It is indicated for the treatment of Crohn's disease, ulcerative colitis, and rheumatoid arthritis and was released as a 120 mg IV formulation.
Compared with IV injections, the SC injection method offers cost‐saving advantages throughout the administration process and potential benefits in effectively utilizing limited hospital facilities and medical staff. 7 The SC injection method also offers time‐saving benefits in terms of overall time taken from consultation to administration of medication to the patient. 8 Therefore, most patients prefer the SC method over IV injections due to the shorter administration time, reduced discomfort, and convenience of medication. 9 , 10 Additionally, unlike IV and intramuscular injection methods, SC injections do not require skilled personnel, enabling self‐administration. 11
One method to further enhance the benefits of SC injections is the use of an autoinjector (AI). A drug injection procedure using an AI for SC injections is convenient for first‐time drug users and has significantly fewer malfunctions related to drug injection. 12 , 13 Moreover, the consistent delivery achieved through an AI reinforces the advantages of the SC injection method via an AI. 14
A majority of the patients who received SC injections via AI reported it as a positive experience, with most of them experiencing no or mild pain during injection, making medication administration acceptable in terms of pain levels. 15 , 16 This is advantageous since the pain experienced by patients during drug administration is closely related to patient compliance, and increased compliance is a key factor in effectively managing an individual's disease. 17 Additionally, the method of administration is closely related to a patient's satisfaction with their treatment. Consequently, the use of an AI for SC self‐administration, compared with a pre‐filled syringe (PFS), showed that treatment compliance and disease state changed with patient satisfaction; higher satisfaction led to increased treatment compliance and a positive ease in disease state. 15
This clinical pharmacology study aimed to develop CT‐P13 120 mg SC administration formulation using an AI and to evaluate its pharmacokinetics (PK) and stability compared with those of a PFS formulation.
METHODS
Ethics
This study complied with the International Council for Harmonization guideline E6(R2) on Good Clinical Practice, and the study protocol adhered to the Declaration of Helsinki and national laws or regulations. The study protocol was approved by the Ministry of Food and Drug Safety of Korea and the Institutional Review Board (IRB) of Chungnam National University Hospital (IRB No. CNUH 2020‐11‐087‐016). The study is registered at Clinical Research Informative Service (KCT0009574).
Participants
All participants provided informed consent using an IRB‐approved consent form before participating in the study, which ensured that they understood and agreed to the research procedures. The study recruited healthy female or male participants aged between 19 and 55 years, with a body weight of 55.0 kg ≤99.9 kg and a body mass index (BMI) of at least 18.0 kg/m2 but not exceeding 29.9 kg/m2. Healthy status was defined as no clinically relevant abnormality through medical history. Participants were included based on medical history, blood pressure, heart rate, physical examination, 12‐lead electrocardiogram tests, and clinical laboratory test results. The major exclusion criteria included participants who had been exposed to infliximab or were currently using biological agents, as well as those with hypersensitivity or allergic reactions to mouse or human proteins or immunoglobulin products.
Study design
This randomized, open‐label, two‐arms, parallel‐group, single‐dose study was conducted at the Clinical Trial Center of Chungnam National University Hospital in Daejeon, Republic of Korea, between February 16, 2021 and July 13, 2021. Participants were randomly assigned to the AI (test drug) or PFS (reference drug) groups in a 1:1 ratio and received a single dose of CT‐P13 SC 120 mg (Figure 1). Blood samples for PK analysis were collected during the in‐house stay period and at outpatient visits, with at least one sample collected during each outpatient visit (After the start of the injection: 2, 6, 24, 48, 72, 96, 108, 120, 132, 144, 156, 168, 192, 215, 240, 288, 336, 672, 1008, 1344, and 2016 h). 18
FIGURE 1.
Study design. Schematic of the research design, illustrating the entire study process for the groups administered with CT‐P13 SC via an autoinjector and a pre‐filled syringe. AI, autoinjector; PFS, pre‐filled syringe; SC, subcutaneous.
Investigational products
CT‐P13 SC is a subcutaneous formulation of concentrated 120 mg/mL infliximab for PFS administration, developed by Celltrion (Incheon, Republic of Korea), which was approved by the European Medicine Agency and the US Food Drug Administration. In this study, CT‐P13 SC was administered using 1‐mL AI or PFS. The CT‐P13 SC AI consists of a needle and needle cover at the top, a cap that covers the needle cover, and a body section with a window for verifying the medicine. The medication is injected by positioning the AI at a 90° angle to the skin and pressing firmly. CT‐P13 SC received Food and Drug Administration approval in October 2023 and is currently marketed under the brand name “ZYMPENTRA”.
Quantitative assay of CT‐P13 concentration and qualitative assay of anti‐CT‐P13 antibodies
The electrochemiluminescent (ECL) method (Meso Scale Diagnostics, LLC, Rockville, MD) was used as a quantitative assay to detect the CT‐P13 serum concentration. PK samples were analyzed using validated immunoassays at the PPD Bioanalytical Laboratory (Richmond, Virginia, USA). The plate was coated with a capture antibody fragment and blocked. The sample was subsequently added allowing the analyte to bind to the blocked plate. A Sulfo‐Tag labeled detection antibody was added and allowed to bind to the analyte. After the addition of read buffer containing tripropylamine, Sulfo‐Tag labeled ruthenium produced a chemiluminescent signal that was triggered when voltage was applied. The signal was proportional to the amount of analyte present in the sample and was captured by the instrument camera. A nominal CT‐P13 concentration range of 100–30,000 ng/mL was chosen to quantitate samples.
The ECL method was used as a qualitative assay to detect anti‐drug antibody (ADA) and neutralizing antibody (NAb) in human serum. Immunogenicity samples were analyzed at the PPD Bioanalytical Laboratory. For ADA, acetic acid was added to the samples to disrupt any antibody complexes. Acid‐treated samples were then neutralized with a buffer containing biotinylated CT‐P13 (Bi‐CT‐P13). The Bi‐CT‐P13/ADA complexes were then bound to a streptavidin‐coated plate and acetic acid was added to release the ADA. The acidified samples were transferred to cluster tubes with neutralization buffer containing Bi‐CT‐P13 and ruthenylated‐CT‐P13 (Ru‐CT‐P13) to form an antibody complex bridge. After incubation, the samples were added to a blocked MSD‐streptavidin (MSD‐SA) plate where the Bi‐CT‐P13 in the complex bound to the streptavidin in the wells, allowing unbound material to be washed away. For NAb, samples were captured with biotin‐CT‐P13 in a neutralization solution after acidification. Any NAb present was bound to the BT‐CT‐P13, and this complex was then bound to a streptavidin plate. The streptavidin plate was acid‐treated to release the NAb. The eluted solution was then transferred to cluster tubes containing neutralization buffer and sulfo‐tag labeled CT‐P13 (ST‐CT‐P13). The solution was transferred in duplicate to an MSD‐ECL plate coated with TNFα and blocked. In the presence of NAb, ST‐CT‐P13 was unable to bind to the TNFα on the plate, resulting in a lower signal being generated after the application of voltage. The resulting ECL signal was inversely proportional to the amount of NAb present in the human serum.
Pharmacokinetic analysis
PK analysis was conducted on all randomized participants who received the entire dose of the study drug and exhibited concentrations exceeding the lower limit of quantification. PK parameters were calculated using noncompartmental methods with Phoenix WinNonlin Version 8.2 (Certara, L.P., Princeton, NJ, USA). The primary PK parameters were the area under the concentration–time curve from time zero to infinity (AUCinf) and maximum serum concentration (C max). The secondary PK parameters were the area under the concentration–time curve from time zero to the last quantifiable concentration (AUClast), time to C max (T max), volume of distribution (Vz/F), terminal elimination half‐life (t 1/2), and clearance (CL/F).
Statistical analysis
The statistical analysis system (SAS) software (SAS Institute, Cary, NC, USA) Version 9.4 was used for all statistical analyses. Log‐transformed AUCinf and C max were determined based on an analysis of covariance (ANCOVA) model with treatment as a fixed effect and stratification factors (sex [male vs. female] and body weight [≥80 kg vs. <80 kg] as measured at randomization) as covariates. 18 The equivalence of PK (AUCinf and C max) was planned to be concluded if the 90% CI (%) for the geometric mean ratio (GMR) was within the equivalence margin of 80%–125% for CT‐P13 SC AI versus CT‐P13 SC PFS. An ANCOVA was conducted for all participants regardless of ADA status and separately for participants by ADA status.
Safety and tolerability assessments
Safety analysis was performed for all randomized participants who received the full or partial dose of infliximab, focusing on the 146 participants who had received the full dose; and 74 participants in the AI and PFS treatment groups, respectively. Safety was assessed via adverse event monitoring, clinical laboratory tests, immunogenicity evaluations, and hypersensitivity reactions, including delayed‐type hypersensitivity, vital signs, 12‐lead electrocardiograms, and local pain at the injection site (using a 100 mm visual analogue scale [VAS]). The VAS assessment was performed for all participants within 15 min following the injection. Specifically, data on systemic injection reactions and localized injection site reactions related to SC injections were collected. Adverse events were classified according to the system organ class and preferred term using MedDRA (version 23.1). Adverse events were aggregated and summarized by treatment group. Additionally, summaries of adverse events, their severity, and their relationship with the treatment were recorded.
RESULTS
Participant demographics
A total of 147 participants were randomized, with 73 and 74 participants assigned to the AI and PFS treatment groups, respectively. Of them, 139 participants completed the study, with 70 and 69 participants in the AI and PFS treatment groups, respectively. Demographic information was summarized on all randomized participants (Table 1). The mean (SD) participant age and BMI at randomization were similar between the two treatment groups; participants in the AI treatment group had a mean age of 26 (5) years and BMI of 23.8 (3.0) kg/m2, while those in the PFS treatment group had a mean age of 27 (6) years and BMI of 24.1 (2.8) kg/m2.
TABLE 1.
Demographics of the study participants.
| CT‐P13 SC autoinjector (N = 73) | CT‐P13 SC pre‐filled syringe (N = 74) | Total (N = 147) | |
|---|---|---|---|
| Age (years) | 26 ± 5 | 27 ± 6 | 26 ± 5 |
| Sex, n (%) | |||
| Male | 61 (83.56) | 61 (82.43) | 122 (82.99) |
| Female | 12 (16.44) | 13 (17.57) | 25 (17.01) |
| Weight (kg) | 71.0 ± 11.6 | 72.1 ± 10.4 | 71.6 ± 11.0 |
| Height (cm) | 172.5 ± 6.8 | 172.8 ± 8.2 | 172.7 ± 7.5 |
| Body mass index (kg/m2) | 23.8 ± 3.0 | 24.1 ± 2.8 | 24.0 ± 2.9 |
Note: Age, weight, height, and body mass index are presented as the mean ± standard deviations. Weight, height, and body mass index represent the outcomes obtained from the screening of the study.
Abbreviation: SC, subcutaneous.
Pharmacokinetics
Of the 147 participants who were randomized, 146 received CT‐P13 SC via AI or PFS, excluding one participant who withdrew before receiving the investigational drug. The 90% CIs (%) of GMR for the AI treatment group‐to‐PFS treatment group ratios of AUCinf and C max were entirely within the predefined equivalence margin of 80%–125% indicating the PK comparability between the groups. The GMR and 90% CIs (%) for the ratios of AUCinf and C max between the AI treatment group‐to‐PFS treatment group were 94.15% (85.02%–104.26%) and 92.48% (84.66%–101.01%), respectively (Table 2).
TABLE 2.
Summary of the pharmacokinetic parameters of CT‐P13 SC autoinjector and pre‐filled syringe treatments.
| Pharmacokinetic parameter | CT‐P13 SC autoinjector (N = 72) | CT‐P13 SC pre‐filled syringe (N = 74) | Total (N = 146) |
|---|---|---|---|
| AUCinf (h∙ng/L) (n = 61) | 5839.8 ± 2059.6 [35.27] | 6283.3 ± 2295.3 [36.53] | 6061.5 ± 2183.0 [36.01] |
| Geometric mean ratio (autoinjector/pre‐filled syringe) | 94.15% (85.02%, 104.26%) | ||
| C max (ng/L) | 13.4 ± 3.5 [26.31] | 14.9 ± 4.9 [32.95] | 14.1 ± 4.3 [30.65] |
| Geometric mean ratio (autoinjector/pre‐filled syringe) | 92.48% (84.66%, 101.01%) | ||
| AUClast (h∙ng/L) | 5124.6 ± 2234.3 [43.60] | 5470.6 ± 2548.1 [46.58] | 5300.0 ± 2396.5 [45.22] |
| T max (h) | 132.1 (72.0, 287.4) | 132.1 (24.0, 287.8) | 132.1 (24.0, 287.8) |
| t 1/2 (h) (n = 61) | 184.1 ± 99.3 [53.942] | 170.1 ± 87.9 [51.66] | 177.1 ± 93.7 [52.87] |
| CL/F (L/h) (n = 61) | 0.02 ± 0.01 [35.59] | 0.02 ± 0.01 [38.46] | 0.02 ± 0.01 [36.97] |
| Vz/F (L) (n = 61) | 5.4 ± 2.2 | 4.7 ± 2.0 | 5.1 ± 2.1 |
| [40.54] | [41.64] | [41.59] | |
Note: Data are presented as the mean ± standard deviation, [coefficient of variation (%)], and (90% Confidence Interval); T max values are median (minimum, maximum). This table summarized the pharmacokinetic parameters of CT‐P13 SC when it was administered via autoinjector and pre‐filled syringe in healthy subjects. The parameters included the area under the concentration–time curve from time zero to infinity (AUCinf), maximum serum concentration (C max), and other key pharmacokinetic metrics such as terminal elimination half‐life (t 1/2) and apparent volume of distribution (Vz/F).
Abbreviations: AUCinf, area under the concentration–time curve from time zero to infinity; AUClast, area under the concentration–time curve from time zero to the last quantifiable concentration; CL/F, apparent clearance after subcutaneous dosing; C max, maximum serum concentration; SC, subcutaneous; t 1/2, terminal elimination half‐life; T max, time to maximum serum concentration; Vz/F, apparent volume of distribution during the terminal phase after non‐intravenous administration.
Moreover, the 90% CIs (%) for the AI treatment group‐to‐PFS treatment groups ratios of AUCinf and C max for participants positive for ADA were entirely within the equivalence margin of 80%–125% predefined for the primary analysis. The AI treatment group‐to‐PFS treatment groups GMR and 90% CIs (%) for the ratios of AUCinf and C max were 94.21% (85.24%–104.13%) and 93.01% (85.02%–101.76%), respectively (Figure 2).
FIGURE 2.
Mean serum concentration of CT‐P13 SC by treatment method and ADA status. Mean (±SD) serum concentrations of CT‐P13 versus time profiles measured by treatment method and ADA status are presented on both (a) linear and (b) semi‐logarithmic scales. The overall trend of the mean serum concentration–time profiles for CT‐P13 was highly similar between the CT‐P13 SC AI and CT‐P13 SC PFS treatment groups in the ADA‐positive state. There was a limitation in the interpretation of serum concentration in the ADA‐negative state owing to the small participant sample size (two [2.78%] participants in the CT‐P13 SC AI and one [1.35%] in the CT‐P13 SC PFS treatment groups). ADA, anti‐drug antibody; AI, autoinjector; PFS, pre‐filled syringe; SC, subcutaneous; SD, standard deviation.
Immunogenicity
No participant was positive for ADA at baseline prior to the study drug administration. At the end of the study, 70 (97.22%) participants in the AI treatment group and 73 (98.65%) participants in the PFS treatment group were positive for ADA, and the proportion of participants with positive ADA results was similar between the CT‐P13 SC AI and CT‐P13 SC PFS treatment groups. All participants with a positive ADA result on Day 56 and at the end of the study were also positive for NAb. At the end of the study, 70 (100%) participants in the AI treatment group and 73 (100%) participants in the PFS treatment group were positive for NAb (Table 3).
TABLE 3.
Immunogenicity reactivity of CT‐P13 SC autoinjector and pre‐filled syringe treatments.
| Visit reactivity | CT‐P13 SC autoinjector (N = 72) | CT‐P13 SC pre‐filled syringe (N = 74) | Total (N = 146) |
|---|---|---|---|
| Anti‐drug antibody result | |||
| Day 0 | |||
| Positive | 0 | 0 | 0 |
| Negative | 72 (100.00) | 74 (100.00) | 146 (100.00) |
| Day 28 | |||
| Positive | 15 (20.83) | 17 (22.97) | 32 (21.92) |
| Negative | 55 (76.39) | 54 (72.97) | 109 (74.66) |
| Day 42 | |||
| Positive | 33 (45.83) | 34 (45.95) | 67 (45.89) |
| Negative | 37 (51.39) | 37 (50.00) | 74 (50.68) |
| Day 56 | |||
| Positive | 54 (75.00) | 54 (72.97) | 108 (73.97) |
| Negative | 16 (22.22) | 16 (21.62) | 32 (21.92) |
| End of study | |||
| Positive | 70 (97.22) | 73 (98.65) | 143 (97.95) |
| Negative | 2 (2.78) | 1 (1.35) | 3 (2.05) |
| Neutralizing antibody result | |||
| Day 0 | |||
| Positive | 0 | 0 | 0 |
| Negative | 0 | 0 | 0 |
| Day 28 | |||
| Positive | 14 (93.33) | 17 (100.00) | 31 (96.88) |
| Negative | 1 (6.67) | 0 | 1 (3.13) |
| Day 42 | |||
| Positive | 32 (96.97) | 34 (100.00) | 66 (98.51) |
| Negative | 1 (3.03) | 0 | 1 (1.49) |
| Day 56 | |||
| Positive | 54 (100.00) | 54 (100.00) | 108 (100.00) |
| Negative | 0 | 0 | 0 |
| End of study | |||
| Positive | 70 (100.00) | 73 (100.00) | 143 (100.00) |
| Negative | 0 | 0 | 0 |
| Anti‐drug antibody status | |||
| At least one anti‐drug antibody‐positive | 70 (97.22) | 73 (98.65) | 143 (97.95) |
| All negative | 2 (2.78) | 1 (1.35) | 3 (2.05) |
Note: Data are presented as the number of participants (percentages). Only participants with positive anti‐drug antibody results were included in the neutralizing antibody summary.
Abbreviation: SC, subcutaneous.
Safety and tolerability
Adverse events were reported in 81 of 146 participants (55.48%); 40 (55.56%) and 41 (55.41%) participants in the AI and PFS groups, respectively. Eighty‐four treatment‐emergent adverse events (TEAEs) were observed in the PFS treatment group, with 27 participants (36.49%) experiencing TEAEs related to the study drug. Eighty‐eight TEAEs were observed in the AI treatment group, with 23 participants (31.94%) experiencing TEAEs related to the study drug. The most frequently reported TEAEs in the AI treatment group were increased C‐reactive protein (CRP) (22 participants, 30.56%) and increased blood creatine phosphokinase (11 participants, 15.28%). While increased CRP (27 participants, 36.49%) was the most common TEAE in the PFS treatment group, followed by increased blood creatine phosphokinase and alanine aminotransferase (nine participants each, 12.16%) (Table 4; Table S2).
TABLE 4.
Summary of adverse events.
| CT‐P13 SC autoinjector (N = 72) | CT‐P13 SC pre‐filled syringe (N = 74) | Total (N = 146) | |
|---|---|---|---|
| Total treatment‐emergent adverse event | |||
| At least one treatment‐emergent adverse event | 40 (55.56) | 41 (55.41) | 81 (55.48) |
| Related to the study drug | 23 (31.94) | 27 (36.49) | 50 (34.25) |
| Unrelated to the study drug | 28 (38.89) | 26 (35.14) | 54 (36.99) |
| At least one treatment‐emergent adverse event classified as infection | 1 (1.39) | 1 (1.35) | 2 (1.37) |
| Total treatment‐emergent serious adverse event | 0 | 0 | 0 |
| Incidence of treatment‐emergent adverse event reported in at least 3% of participants in any treatment group | |||
| Investigations | |||
| Alanine aminotransferase increased | 10 (13.89) | 9 (12.16) | 19 (13.01) |
| Aspartate aminotransferase increased | 6 (8.33) | 5 (6.76) | 11 (7.53) |
| Blood bilirubin increased | 4 (5.56) | 2 (2.70) | 6 (4.11) |
| Blood creatine phosphokinase‐MB increased | 4 (5.56) | 3 (4.05) | 7 (4.79) |
| Blood creatine phosphokinase increased | 11 (15.28) | 9 (12.16) | 20 (13.70) |
| C‐reactive protein increased | 22 (30.56) | 27 (36.49) | 49 (33.56) |
| Gamma‐glutamyl transferase increased | 3 (4.17) | 2 (2.70) | 5 (3.42) |
| Red blood cell‐positive urine | 3 (4.17) | 2 (2.70) | 5 (3.42) |
| Troponin I increased | 3 (4.17) | 1 (1.35) | 4 (2.74) |
| White blood cell‐positive urine | 3 (4.17) | 2 (2.70) | 5 (3.42) |
| Nervous system disorders | |||
| Headache | 0 | 3 (4.05) | 3 (2.05) |
Note: Data are presented as the number of participants (percentage).
Abbreviation: SC, subcutaneous.
No TEAEs were classified as localized injection site reactions and systemic injection reaction occurred. The mean (SD) local injection site pain assessed by VAS was 8.89 mm (12.65 mm) in the AI treatment group and 9.15 mm (14.99 mm) in the PFS treatment group (Table S1).
No apparent treatment‐related trends in vital signs, clinical laboratory results, physical examination findings, or ECG results were observed across all treatment groups.
DISCUSSION
The GMR and 90% CI for the AUCinf between the infliximab AI and PFS administration groups was 94.15% (85.02%–104.26%), and the C max was 92.48% (84.66%–101.01%), indicating that the PK was comparable between the groups because the 90% CI was within the predefined equivalence margin of 80%–125% (Figure 3). Similar to other PK studies comparing PFS and AI of biosimilars, no PK differences were observed in administration between the AI and PFS methods. 19 , 20 , 21 , 22
FIGURE 3.
Mean serum concentration of CT‐P13 SC by treatment method. Mean (± SD) serum concentrations of CT‐P13 versus time profiles measured by treatment method are presented on both (a) linear and (b) semi‐logarithmic scales. Following single SC administration of 120 mg CT‐P13 SC AI or CT‐P13 SC PFS, the overall trend of the mean serum concentration–time profiles for CT‐P13 during the in‐house stay and the whole study period was similar between the CT‐P13 SC AI and CT‐P13 SC PFS treatment groups. AI, autoinjector; PFS, pre‐filled syringe; SC, subcutaneous; SD, standard deviation.
In terms of safety, 81 participants (55.48%) experienced TEAEs, with the intensity (CTCAE v5.0) of most adverse events being grade I or II, and a similar proportion of participants experiencing TEAEs across both administration groups; 40 and 41 participants in AI and PFS treatment group, respectively. Compared with other CT‐P13 studies, no notable difference was observed in the occurrence of TEAEs, 18 Additionally, the VAS assessment for the safety evaluation of SC injection showed no major difference between the AI and PFS administration groups. This aligns with other studies where no notable safety differences were observed owing to the method of drug delivery between the AI and PFS administration groups in terms of safety and related comparisons. 22 , 23
Moreover, our results showed no differences in PK and safety between the PFS and AI forms of the same drug formulation, which could provide noteworthy and positive options for patients. Studies on self‐administration by patients using the AI method have shown that there were no difficulties in using the device regardless of experience, potentially improving treatment adherence. 24 Additionally, adherence is a critical factor in clinical practice for treating/managing a patient's condition. Studies analyzing the impact of adherence on treatment outcomes showed a 26% difference in experiencing good treatment effects based on adherence, underscoring the importance of considering drug adherence for patients. 25 , 26
Other studies comparing PFS and AI administration methods have shown that most participants prefer the AI method over a PFS in terms of usability and convenience, adding credibility to the option of administering medication via an AI as a positive choice for patients. 27 , 28
Despite the positive results, one limitation of this study was the small sample size of ADA‐negative participants, which presented challenges in evaluating changes based on the ADA state.
In conclusion, no clinically significant differences were observed in the PK, safety, or tolerability for CT‐P13 SC administered via PFS compared with AI administration. This suggests that the use of AI for self‐administration of infliximab could be positively considered for patients.
AUTHOR CONTRIBUTIONS
Y.C.P. wrote the manuscript. J.H.K., J.H.H., and J.‐G.J. designed the research. J.H.K., S.H.K., J.H.L., J.H.H., and J.‐G.J. performed the research. Y.C.P. and J.S. analyzed the data. Y.C.P., J.H.K, and J.S. contributed new reagents/analytical tools.
FUNDING INFORMATION
The study was funded by Celltrion, Inc. (Incheon, Republic of Korea).
CONFLICT OF INTEREST STATEMENT
S.H.K. is an employee of Celltrion, Inc. and has received stock/stock options from Celltrion, Inc. J.H.L. is an employee of Celltrion, Inc. All other authors declared no competing interests for this work.
Supporting information
Tables S1‐S2
Park YC, Kim JH, Kim SH, et al. Pharmacokinetic comparison of subcutaneously administered CT‐P13 (biosimilar of infliximab) via autoinjector and pre‐filled syringe in healthy participants. Clin Transl Sci. 2024;17:e70037. doi: 10.1111/cts.70037
Contributor Information
Jin‐Gyu Jung, Email: jjg72@cnuh.co.kr.
Jung Sunwoo, Email: swj4991@cnuh.co.kr.
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Associated Data
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Supplementary Materials
Tables S1‐S2