https://orcid.org/0000-0003-0921-7225
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ABSTRACT
Background
This study compared the pharmacokinetics (PK), immunogenicity, and safety of candidate tocilizumab biosimilar, CT-P47, administered via auto-injector (CT-P47 AI) or pre-filled syringe (CT-P47 PFS), in healthy Asian adults.
Research design and methods
In this phase I, multicenter, open-label study, participants were randomized 1:1 to receive a single 162 mg/0.9 mL dose of CT-P47 via AI or PFS. Primary endpoints were area under the concentration – time curve from time zero to infinity (AUC0–inf) and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the predefined 80–125% equivalence margin. Secondary PK parameters, immunogenicity, and safety outcomes were also assessed.
Results
Of 314 participants randomized (155 CT-P47 AI; 159 CT-P47 PFS), 310 received the study drug (153 CT-P47 AI; 157 CT-P47 PFS). Primary and secondary PK results, immunogenicity and safety were similar between groups. Ninety percent CIs for the ratio of gLSMs were within the predefined equivalence margin for AUC0–inf (85.87–102.94) and Cmax (82.98–98.16).
Conclusions
PK equivalence between CT-P47 AI and CT-P47 PFS was demonstrated in healthy Asian adults, with comparable immunogenicity and safety between the two devices.
Trial registration
ClinicalTrials.gov: NCT05617183.
Plain Language Summary
Tocilizumab is a biologic medicine used to treat inflammatory diseases, such as rheumatoid arthritis. A biosimilar is a drug that is an almost identical copy of an approved original (‘reference’) biologic medicine; it has identical efficacy and safety to the original medicine but is typically less expensive. CT‑P47 is in development as a possible tocilizumab biosimilar.
Some patients prefer injections using an auto-injector (AI) rather than a pre-filled syringe (PFS), for reasons including ease of use and convenience. With an AI, medicine is delivered automatically by firmly pressing the device against the skin, whereas, with a PFS, a needle is inserted into the skin and medicine delivered by depressing the plunger. The injection of CT‑P47 using a PFS has shown comparable pharmacokinetics (i.e., the uptake, metabolism and excretion of the drug by the body) and safety to tocilizumab. Therefore, if the pharmacokinetics and safety of CT‑P47 administered via AI and PFS were shown to be similar, this might expand the choice of administration devices available to patients.
In this study, 310 healthy adults received a single injection of CT‑P47 via AI or PFS. Blood samples were taken over 43 days to analyze pharmacokinetics. The uptake, metabolism and elimination of CT‑P47 by the body was similar when administered by each device, suggesting that CT‑P47 can be administered by either AI or PFS.
Abbreviations
| %AUCext | = | Percentage of AUC0–inf obtained by extrapolation |
| ADA | = | Anti‑drug antibody |
| AE | = | Adverse event |
| AI | = | Auto-injector |
| ANCOVA | = | Analysis of covariance |
| AUC0–inf | = | Area under the concentration – time curve from time zero to infinity |
| AUC0–last | = | Area under the concentration – time curve from time zero to the last quantifiable concentration |
| BLQ | = | Below the lower limit of quantification |
| BMI | = | Body mass index |
| CI | = | Confidence interval |
| CL/F | = | Apparent total body clearance |
| Cmax | = | Maximum serum concentration |
| CV% | = | Coefficient of variation |
| ECL | = | Electrochemiluminescence |
| EMA | = | European Medicines Agency |
| EOS | = | End-of-study |
| EU | = | European Union |
| FDA | = | Food and Drug Administration |
| gLSM | = | Geometric least-squares mean |
| IL-6R | = | Interleukin-6 receptor |
| ISR | = | Injection site reaction |
| IV | = | Intravenous |
| LSM | = | Least-squares mean |
| NAb | = | Neutralizing antibody |
| PFS | = | Pre-filled syringe |
| PK | = | Pharmacokinetic |
| RA | = | Rheumatoid arthritis |
| SC | = | Subcutaneous |
| SD | = | Standard deviation |
| t½ | = | Terminal half-life |
| TEAE | = | Treatment-emergent adverse event |
| TEAESI | = | Treatment-emergent adverse event of special interest |
| TESAE | = | Treatment-emergent serious adverse event |
| Tmax | = | Time to maximum serum concentration |
| VAS | = | Visual analog scale |
| Vz/F | = | Apparent volume of distribution during the terminal phase |
| λz | = | Terminal elimination rate constant |
Declaration of interest
KS Yu, H Ryu, D Shin, MK Park, JG Hwang, SJ Moon, and MG Kim have nothing to disclose, other than sponsorship with respect to the current study by Celltrion, Inc. E Keystone has had consulting agreements and/or held advisory board membership for AbbVie, Celltrion, GSK, Lilly, Pfizer, Sandoz, and Samsung Bioepsis, and has received honoraria for speaking agreements with AbbVie, Celltrion, GSK, Lilly, Pfizer, and Sandoz. JS Smolen has received grants for his institution from AbbVie, AstraZeneca, Janssen, Lilly, Novartis, and Roche, and has received honoraria for consulting or speaking engagements from AbbVie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB. SH Kim, YJ Bae, DB Jeon, JY Jang, GE Yang, JH Bae and JY Lee are employees of Celltrion, Inc. GR Burmester has received honoraria for consulting and lectures from AbbVie, Chugai, Galapagos, Lilly, Pfizer, Roche, and Sanofi. The authors have no other 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 apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
All authors contributed to study design and data analysis or interpretation. KS Yu, H Ryu, D Shin, MK Park, JG Hwang, SJ Moon, MG Kim, SH Kim, YJ Bae, DB Jeon, JY Jang, GE Yang, JH Bae, and JY Lee contributed to data collection. All authors critically reviewed and critically revised the manuscript, approved the final version for publication and agree to be accountable for the accuracy and integrity of the work.
Ethical approval
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guideline. All national, state, and local laws and regulations were followed. The study protocol, informed consent form, advertisements used for the recruitment of participants and any other written materials provided to participants were approved by the relevant institutional review board(s) (Table S1) prior to study initiation. Participants provided written informed consent prior to study enrollment.
Acknowledgments
We thank all participants and investigators involved in the study. Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, collating author comments, copyediting, fact checking, and referencing, was provided by Samantha Booth, at Aspire Scientific Limited (Bollington, UK). Funding for medical writing support for this article was provided by Celltrion, Inc. (Incheon, Republic of Korea). This study was pre-registered with ClinicalTrials.gov [NCT05617183].
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Supplemental data
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2024.2321360.