In Study 7 (metastatic gastric cancer), of the 294 patients treated with trastuzumab, 108 (37%) were 65 years ofage or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed.
10 OVERDOSAGE
There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not
been tested.
11 DESCRIPTION
Trastuzumab-qyyp is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity tothe extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab-qyyp isproduced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture.
TRAZIMERA (trastuzumab-qyyp) for injection is a sterile, white, preservative-free lyophilized powder with acake-like appearance, for intravenous administration.
Each multiple-dose vial of TRAZIMERA delivers 420 mg trastuzumab-qyyp, 7.9 mg L-histidine, 9.5 mgL-histidine HCl monohydrate, 1.7 mg polysorbate 20, and 386 mg sucrose. Reconstitution with 20 mL of theappropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab-qyyp that delivers 20mL (420 mg trastuzumab-qyyp), at a pH of approximately 6. If TRAZIMERA is reconstituted with SWFIwithout preservative, the reconstituted solution is considered single-dose.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which isstructurally related to the epidermal growth factor receptor. Trastuzumab products have been shown, in both invitro 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, trastuzumabproduct-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cellscompared with cancer cells that do not overexpress HER2.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, wereeva luated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on theQTc interval duration and there was no apparent relationship between serum trastuzumab concentrations andchange inQTcF interval duration in patients with HER2 positive solid tumors.
12.3 Pharmacokinetics
The pharmacokinetics of trastuzumab were eva luated in a pooled population pharmacokinetic (PK) modelanalysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receivingintravenous trastuzumab. Total trastuzumab clearance increases with decreasing concentrations due to parallellinear and non-linear elimination pathways.
Although the average trastuzumab exposure was higher following the first cycle in breast cancer patientsreceiving 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 cycleand at steady state as well as the time to steady state was higher in breast cancer patients compared to MGCpatients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted
trastuzumab exposure and PK parameters following the first tra