Published in:
01-12-2014 | Original Research Article
A Phase I Dose-Escalation and Bioequivalence Study of a Trastuzumab Biosimilar in Healthy Male Volunteers
Published in: Clinical Drug Investigation | Issue 12/2014
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Background
Trastuzumab (Herceptin®) is a humanized monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of HER2-overexpressing breast and gastric cancer. FTMB is being developed as a biosimilar of trastuzumab.
Objective
In this combined dose-escalation and bioequivalence study of parallel design, the pharmacokinetic profile of FTMB was compared with Herceptin®.
Methods
Healthy male volunteers received single doses of 0.5, 1.5, 3.0 or 6.0 mg/kg FTMB, or placebo, in consecutive dose-escalation cohorts to assess the safety profile. Thereafter, the 6 mg/kg cohort was expanded to establish bioequivalence between FTMB (Test) and Herceptin® (Reference) based on an acceptance interval of 80.0–125.0 %. In total, 118 subjects were enrolled in the study.
Result
The mean area under the concentration–time curve from time zero to infinity (AUC∞) was 1,609 µg·day/mL (Test) and 1,330 µg·day/mL (Reference). The log-transformed geometric mean Test/Reference (T/R) ratio for AUC∞ was 89.6 % (90 % confidence interval [CI] 85.1–94.4), demonstrating bioequivalence. For the secondary endpoint, the maximum concentration observed (C
max), the geometric mean T/R ratio was 89.4 % (90 % CI 83.4–95.9). Non-linear, target-mediated pharmacokinetics were also observed. Adverse events other than the documented side effects of Herceptin® (fever, influenza-like illness, and fatigue) did not occur. No signs of cardiotoxicity were observed.
Conclusions
This bioequivalence study with a trastuzumab biosimilar in healthy male volunteers demonstrated bioequivalence of FTMB with Herceptin®. FTMB was well tolerated in doses up to 6 mg/kg. Non-linear target elimination was also observed in the pharmacokinetic profile of trastuzumab.