A Phase I Dose-Escalation and Bioequivalence Study of a Trastuzumab Biosimilar in Healthy Male Volunteers

Background Trastuzumab (Herceptin (R)) 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 bio-equivalence study of parallel design, the pharmacokinetic profile of FTMB was compared with Herceptin (R). 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 (R) (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(infinity)) was 1,609 mu g.day/mL (Test) and 1,330 mu g.day/mL (Reference). The log-transformed geometric mean Test/Reference (T/R) ratio for AUC(infinity) 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 (R) (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 (R). FTMB was well tolerated in doses up to 6 mg/kg. Non-linear target elimination was also observed in the pharmacokinetic profile of trastuzumab.