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

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

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

In patients with metastatic gastric cancer (Study 7), mean serum trastuzumab trough concentrations at steady state were 24 to 63% lower as compared to the concentrations observed in patients with breast cancer receiving treatment for metastatic disease in combination with paclitaxel, as monotherapy for metastatic disease, or as adjuvant monotherapy.

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 1880ng/mL (median 11ng/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 (≤ 2.0mg creatinine/dL).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Herceptin has not been tested for carcinogenic potential.

No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118mg/kg Herceptin.

A fertility study conducted in female cynomolgus monkeys at doses up to 25times the weekly recommended human dose of 2mg/kg trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. Studies to eva luate the effects of trastuzumab on male fertility have not been conducted.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies

Reproductive toxicology studies have been conducted in cynomolgus monkeys at doses up to 25times the weekly recommended human dose of 2mg/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. Plac