d AUC at steady state over a three-week period was three times 578 mg•day/l (1677 mg•day/l) with 3 weekly doses of 2 mg/kg and 1793 mg day/l with one every three week dose of 6 mg/kg; the estimated median peak concentrations were 104 mg/l and 189 mg/l and the trough concentrations were 64.9 mg/l and 47.3 mg/l, respectively. In patients with early breast cancer administered Herceptin at a loading dose of 8 mg/kg followed every three weeks by 6 mg/kg, using model-independent or non-compartmental analyses (NCA) the mean steady state trough concentration measured at cycle 13 (week 37) was 63 mg/l, which was comparable to that reported previously in patients with metastatic breast cancer receiving the weekly regimen.
Clearance (CL)
The typical trastuzumab clearance (for a body weight of 68 kg) was 0.241 l/day.
The effects of patient characteristics (such as age or serum creatinine) on the disposition of trastuzumab have been eva luated. The data suggest that the disposition of trastuzumab is not altered in any of these groups of patients (see section 4.2), however, studies were not specifically designed to investigate the impact of renal impairment upon pharmacokinetics.
Volume of distribution
In all clinical studies, the volume of distribution of the central (Vc) and the peripheral (Vp) compartment was 3.02 l and 2.68 l, respectively, in the typical patient.
Circulating shed antigen
Detectable concentrations of the circulating extracellular domain of the HER2 receptor (shed antigen) are found in the serum of some patients with HER2 overexpressing breast cancers. Determination of shed antigen in baseline serum samples revealed that 64 % (286/447) of patients had detectable 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 of trastuzumab. However, with weekly dosing, most patients with elevated shed antigen levels achieved target serum concentrations of trastuzumab by week 6 and no significant relationship has been observed between baseline shed antigen and clinical response.
Advanced Gastric Cancer
Steady state pharmacokinetics
A two compartment nonlinear population pharmacokinetic model, based on data from Phase III study BO18255, was used to estimate the steady state pharmacokinetics in patients with advanced gastric cancer administered trastuzumab at a loading dose of 8 mg/kg followed by a 3-weekly maintenance dose of 6 mg/kg. The observed serum levels of trastuzumab were lower and thus total clearance was estimated to be higher in AGC patients compared to breast cancer patients receiving the same dosing regimen. The reason for this is unknown. At high concentrations, total clearance is dominated by linear clearance, and the half-life in AGC patients is approximately 26 days. The median predicted steady-state AUC values (over a period of 3 weeks at steady state) is equal to 1213 mg•day/L, the median steady-state Cmax is equal to 132 mg/l and the median steady-state Cmin values is equal to 27.6 mg/L.
There are no data on the level of circulating extracellular domain of the HER2 receptor (shed antigen) in the serum of gastric cancer patients.
5.3 Preclinical safety data
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or reproductive toxicity in teratology, female fertility or late gestational toxicity/placental tran
