Mechanism of Action

The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Herceptin has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.

Herceptin is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Herceptin-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Pharmacokinetics

The pharmacokinetics of trastuzumab were studied in women with metastatic breast cancer. Short duration intravenous infusions of 10 to 500 mg Herceptin once weekly demonstrated dose-dependent pharmacokinetics. Mean half-life increased and clearance decreased with increasing dose level. The half-life averaged 2 and 12 days at the 10 and 500 mg dose levels, respectively. The volume of distribution of trastuzumab was approximately that of serum volume (44 mL/kg). At the highest weekly dose studied (500 mg), mean peak serum concentrations were 377 mcg/mL.

In studies using an initial dose of 4 mg/kg followed by a weekly dose of 2 mg/kg, a mean half-life of 6 days (range 1-32 days) was observed. Between weeks 16 and 32, trastuzumab serum concentrations reached a steady state with mean trough and peak concentrations of approximately 79 mcg/mL and 123 mcg/mL, respectively.

In a study of women receiving adjuvant therapy for breast cancer, a mean half-life of trastuzumab of 16 days (range: 11-23 days) was observed after an initial dose of 8 mg/kg followed by a dose of 6 mg/kg every three weeks. Between weeks 6 and 37, trastuzumab serum concentrations reached a steady-state with mean trough and peak concentrations of 63 mcg/mL and 216 mcg/mL, respectively.

Sixty-four percent (286/447) of women with metastatic breast cancer had detectable circulating extracellular domain of the HER2 receptor (shed antigen), which ranged as high as 1880 ng/mL (median 11 ng/mL). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations.

Data suggest that the disposition of trastuzumab is not altered based on age or serum creatinine ( ≤ 2.0 mg creatinine/dL).

Mean serum trough concentrations of trastuzumab, when administered in combination with paclitaxel, were consistently elevated approximately 1.5-fold as compared with serum concentrations of trastuzumab when used in combination with anthracycline plus cyclophosphamide. In clinical studies in HER2+ metastatic breast cancer where Herceptin was administered in combination with paclitaxel, in combination with docetaxel, or in combination with paclitaxel and doxorubicin, Herceptin did not appear to alter the plasma concentrations of these chemotherapeutic agents, or the metabolites that were analyzed.

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproductive toxicology studies have been conducted in cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg Herceptin and have revealed no evidence of impaired fertility or harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of Herceptin during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetal development period was observed in monkeys.

Clinical Studies

Adjuvant Breast Cancer

The safety and efficacy of Herceptin in women receiving adjuvant chemotherapy for HER-2 overexpressing breast cancer, were evaluated in an integrated analysis of two randomized, open-label, clinical trials (Studies 1 and 2) with a total of 3752 women and in a third randomized, open-label, clinical trial (Study 3) with a total of 3386 women.

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