title: 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.
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 T(max) of 72 (range, 36-144) hours and eliminated with mean (%CV) t(½) of 92.7 (20.9%) and 87.4 (16.6%) hours, respectively. The GMRs (90% CIs) of the test to reference drug for C(max), AUC(0-t), and AUC(0-∞) 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.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Namyi
authors.initials: N
authors.lastname: Gu
authors.forename: Sojeong
authors.initials: S
authors.lastname: Yi
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Kim
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Kim
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People; D059451:Biosimilar Pharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D056910:Republic of Korea; D012737:Sex Factors; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept