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. Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.
Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.
The pharmacokinetics of trastuzumab were evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways.
Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the three-weekly schedule compared to the weekly schedule of trastuzumab, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first trastuzumab cycle and at steady state exposure are described in Tables 7 and 8, respectively.
Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations in at least 95% of breast cancer patients and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
| Schedule | Primary tumor type | N | Cmin (µg/mL) | Cmax (µg/mL) | AUC0–21 days (µg.day/mL) |
|---|---|---|---|---|---|
| 8 mg/kg + 6 mg/kg q3w | Breast cancer | 1195 | 29.4 (5.8 to 59.5) | 178 (117 to 291) | 1373 (736 to 2245) |
| MGC | 274 | 23.1 (6.1 to 50.3) | 132 (84.2 to 225) | 1109 (588 to 1938) | |
| 4 mg/kg + 2 mg/kg qw | Breast cancer | 1195 | 37.7 (12.3 to 70.9) | 88.3 (58 to 144) | 1066 (586 to 1754) |
| Schedule | Primary tumor type | N | Cmin,ss* (µg/mL) | Cmax,ss† (µg/mL) | AUCss, 0–21 days (µg.day/mL) | Time to steady-state (week) | Total CL range at steady-state (L/day) |
|---|---|---|---|---|---|---|---|
| 8 mg/kg + 6 mg/kg q3w | Breast cancer | 1195 | 47.4 (5 to 115) | 179 (107 to 309) | 1794 (673 to 3618) | 12 | 0.173 to 0.283 |
| MGC | 274 | 32.9 (6.1 to 88.9) | 131 (72.5 to 251) | 1338 (557 to 2875) | 9 | 0.189 to 0.337 | |
| 4 mg/kg + 2 mg/kg qw | Breast cancer | 1195 | 66.1 (14.9 to 142) | 109 (51.0 to 209) | 1765 (647 to 3578) | 12 | 0.201 to 0.244 |
Specific Populations
Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (<65 (n = 1294); ≥65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab products in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment are unknown.
Drug Interaction Studies
There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinically significant interactions between trastuzumab and concomitant medications used in clinical trials have not been observed.
Paclitaxel and Doxorubicin
Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy.
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. Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.
Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.
The pharmacokinetics of trastuzumab were evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways.
Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the three-weekly schedule compared to the weekly schedule of trastuzumab, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first trastuzumab cycle and at steady state exposure are described in Tables 7 and 8, respectively.
Population PK based simulations indicate that following discontinuation of trastuzumab, concentrations in at least 95% of breast cancer patients and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
| Schedule | Primary tumor type | N | Cmin (µg/mL) | Cmax (µg/mL) | AUC0–21 days (µg.day/mL) |
|---|---|---|---|---|---|
| 8 mg/kg + 6 mg/kg q3w | Breast cancer | 1195 | 29.4 (5.8 to 59.5) | 178 (117 to 291) | 1373 (736 to 2245) |
| MGC | 274 | 23.1 (6.1 to 50.3) | 132 (84.2 to 225) | 1109 (588 to 1938) | |
| 4 mg/kg + 2 mg/kg qw | Breast cancer | 1195 | 37.7 (12.3 to 70.9) | 88.3 (58 to 144) | 1066 (586 to 1754) |
| Schedule | Primary tumor type | N | Cmin,ss* (µg/mL) | Cmax,ss† (µg/mL) | AUCss, 0–21 days (µg.day/mL) | Time to steady-state (week) | Total CL range at steady-state (L/day) |
|---|---|---|---|---|---|---|---|
| 8 mg/kg + 6 mg/kg q3w | Breast cancer | 1195 | 47.4 (5 to 115) | 179 (107 to 309) | 1794 (673 to 3618) | 12 | 0.173 to 0.283 |
| MGC | 274 | 32.9 (6.1 to 88.9) | 131 (72.5 to 251) | 1338 (557 to 2875) | 9 | 0.189 to 0.337 | |
| 4 mg/kg + 2 mg/kg qw | Breast cancer | 1195 | 66.1 (14.9 to 142) | 109 (51.0 to 209) | 1765 (647 to 3578) | 12 | 0.201 to 0.244 |
Specific Populations
Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (<65 (n = 1294); ≥65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab products in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment are unknown.
Drug Interaction Studies
There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinically significant interactions between trastuzumab and concomitant medications used in clinical trials have not been observed.
Paclitaxel and Doxorubicin
Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy.
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