A phase I dose-escalation and bioequivalence study of a trastuzumab biosimilar in healthy male volunteers.
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.


RESULTS
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 (Cmax), 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.
Synthon Biopharmaceuticals, Microweg 22, 6545 CN, Nijmegen, The Netherlands, Liselijn.Wisman@synthon.com.
Liselijn A B
LA
Wisman
Eduard P M
EP
De Cock
Joannes A A
JA
Reijers
Ingrid M C
IM
Kamerling
Sandra H G
SH
Van Os
Marieke L
ML
de Kam
Jacobus
J
Burggraaf
Gerrit
G
Voortman
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D059451:Biosimilar Pharmaceuticals / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D015331:Cohort Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D016037:Single-Blind Method; D013810:Therapeutic Equivalency; D000068878:Trastuzumab; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; D059451:Biosimilar Pharmaceuticals; D000068878:Trastuzumab