Elsevier

Clinical Therapeutics

Volume 33, Issue 12, December 2011, Pages 2029-2037
Clinical Therapeutics

Pharmacokintetics, bioavailability, & bioequivalence
Original research
Comparative Pharmacokinetics and Tolerability of Branded Etanercept (25 mg) and Its Biosimilar (25 mg): A Randomized, Open-Label, Single-Dose, Two-Sequence, Crossover Study in Healthy Korean Male Volunteers

https://doi.org/10.1016/j.clinthera.2011.10.022Get rights and content

Abstract

Background

The biosimilar is a recombinant dimeric tumor necrosis factor receptor (TNFR) under development for the treatment of rheumatoid arthritis.

Objective

The aim of this study was to compare the pharmacokinetics and/or tolerability of branded etanercept and its biosimilar in healthy Korean men before investigating the clinical efficacy of the biosimilar in subjects.

Methods

Etanercept (reference, 25 mg) or its biosimilar (test, 25 mg) was subcutaneously injected to the periumbilical area of healthy volunteers in a randomized, open-label, single-dose, active-controlled, two-sequence, crossover study. Plasma concentrations of TNFR in serial blood samples for 480 hours after dosing were measured by ELISA. The primary outcome, pharmacokinetic characteristics, was assessed via geometric mean ratios (GMRs) of the log-transformed pharmacokinetic parameters. The second outcome, tolerability, was evaluated using physical examinations, electrocardiograms, clinical laboratory tests, vital sign measurements, and adverse events (AEs) by unmasked investigators.

Results

Twenty-three men of mean age (%CV) 25.8 years (17.1%) and weight 70.5 kg (12.8%) were administered study medication. Four subjects dropped out after the first period; their data were included in the analysis. Both test and reference drugs were absorbed with a median Tmax of 72 (range, 36–144) hours and eliminated with mean (%CV) t½ of 92.7 (20.9%) and 87.4 (16.6%) hours, respectively. The GMRs (90% CIs) of the test to reference drug for Cmax, AUC0–t, and AUC0–∞ were 0.99 (0.83–1.17), 0.95 (0.79–1.13), and 0.95 (0.80–1.13), respectively. Eleven of 21 (52.4%) and 8 of 21 (38.1%) subjects administered the test and reference drugs reported 22 and 21 AEs, respectively. Common AEs were headache (14.3%), throat irritation (8.5%), and epistaxis (9.5%). Three serious AEs related to a traffic accident (back, neck, and musculoskeletal pain) were reported in a test drug–treated subject.

Conclusions

In this select group of Korean healthy male volunteers, the reference drug and the test biosimilar met the standard criteria for assuming bioequivalence as defined by Korean regulatory authorities. Because the reference drug is a biological product, further trials for assessment of its efficacy are still required by Korean authorities. World Health Organization International Clinical Trials Registry Platform identifier: KCT0000118

Introduction

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that is principally characterized by the destruction and ankylosis of synovial joints. Tumor necrosis factor (TNF) has been identified as a key regulator of abnormal immune inflammatory responses in RA. TNF has inflammation-associated bioactivities, such as the induction of synovial fibroblast proliferation and the stimulation of fibroblasts and chondrocytes to secrete prostaglandin E2 and collagenase.1, 2, 3 After a demonstration of an increase of TNF in the synovial fluid of RA patients4 and the improvement of their clinical outcomes by blocking TNF,5 various TNF inhibitors, such as etanercept, infliximab, adalimumab, golimumab,§ and certolizumab, were developed as treatments for RA.6

The test drug is a biological product developed to be a biosimilar version of etanercept (reference). It consists of etanercept, a fusion protein combining the 75-kDa dimeric human extracellular binding domain of the TNF receptor (TNFR; N-terminal 235 amino acids), and the Fc domain of human immunoglobulin-G1, including CH3, CH2, and the hinge region (232 amino acids), and is produced in genetically engineered Chinese hamster ovary cells.

The pharmacokinetic properties of etanercept in Koreans have not been previously reported nor has the biosimilar product been noted in the PubMed.gov online search engine.7 The objective of this study was to compare the pharmacokinetic properties and tolerability between branded and biosimilar etanercept 25 mg after a single subcutaneous administration in healthy Korean volunteers before investigating the clinical efficacy of the biosimilar etanercept in rheumatic patients as a clinical development in New Drug Application packages.

Section snippets

Subjects

Healthy Korean male volunteers aged 20 to 55 years were eligible for this study. Volunteers were judged to be healthy based on a medical history, physical examinations, vital sign measurements (including pulse rates, and systolic and diastolic blood pressures in sitting positions measured with a noninvasive blood pressure module [GE Healthcare, Milwaukee, Wisconsin]), tympanic body temperatures, 12-lead electrocardiograms (ECGs) and clinical laboratory tests (clinical chemistry, hematology, and

Demographic Characteristics

Twenty-five healthy Korean men were enrolled in this study and randomized to 2 sequence groups. Two subjects in the “reference/test” sequence group withdrew consent before study drug administration; therefore, 23 subjects (12 in the “test/reference” group and 11 in the “reference/test” group) were administered study drug at least once. After the administration of the study drugs, 19 of 23 subjects completed the study, with 1 and 3 dropouts in the “test/reference” and “reference/test” groups,

Discussion

This study was conducted to compare the pharmacokinetic properties and tolerability of branded etanercept 25 mg and the same dose of its biosimilar after a single subcutaneous administration in healthy volunteers before the evaluation of the biosimilar clinical efficacy and safety in rheumatic patients. Branded etanercept and its test biosimilar met the standard criteria for assuming bioequivalence as defined by Korean regulatory authorities in this small select group of Korean healthy male

Conclusions

In this select group of Korean healthy male volunteers, branded etanercept and its test biosimilar were well tolerated and met the standard criteria for assuming bioequivalence as defined by Korean regulatory authorities. The clinical efficacy and safety of biosimilar etanercept should be evaluated in further studies in RA patients.

Conflicts of Interest

SNUH was contracted by the sponsors to design, conduct, analyze, and report this investigation. All authors are employees of SNUH and worked as investigators in the Department of Pharmacology and Clinical Pharmacology, SNUH. None of the authors has any intellectual property rights or significant financial interest in the test product, including equity interests. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

Acknowledgments

This study was sponsored by Mycenax Biotech Inc., Miaoli, Taiwan, and Biotrion, Seongnam, Republic of Korea. Mycenax Biotech Inc quantified the serum etanercept concentrations and Biotrion approved the manuscript. The sponsor did not participate in other performances, including study design, data gathering, and data analysis (including tolerability and pharmacokinetics), or writing the manuscript. Randomization, monitoring, and data management were performed by LSK Global Pharma Services Co.,

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