Trastuzumab - How It Works
Clinical pharmacology details from the US FDA-approved label: how Trastuzumab works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling pathway in human tumor cells that overexpress HER2. Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. While pertuzumab alone in
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4.
As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K).
Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively.
Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling pathway in human tumor cells that overexpress HER2.
Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.
Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue.
It is depolymerized by the naturally occurring enzyme hyaluronidase.
Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days.
Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan.
In the doses administered, hyaluronidase in PHESGO acts transiently and locally.
The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.
Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into the systemic circulation when given in the subcutis of Göttingen Minipigs.
12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of pertuzumab and trastuzumab in PHESGO have not been fully characterized.
Cardiac Electrophysiology The effect of intravenous pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2-positive breast cancer (NCT00567190).
No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial.
A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.
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.
12.3 Pharmacokinetics The pharmacokinetics (PK) of pertuzumab and trastuzumab were characterized in the FeDeriCa trial following subcutaneous administration of PHESGO (1200 mg pertuzumab/600 mg trastuzumab initial dose followed by 600 mg pertuzumab/600 mg trastuzumab every 3 weeks) and intravenous administration of pertuzumab and trastuzumab (840 mg pertuzumab/8 mg/kg trastuzumab initial dose followed by 420 mg pertuzumab/6 mg/kg trastuzumab every 3 weeks).
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics (PK) of pertuzumab and trastuzumab were characterized in the FeDeriCa trial following subcutaneous administration of PHESGO (1200 mg pertuzumab/600 mg trastuzumab initial dose followed by 600 mg pertuzumab/600 mg trastuzumab every 3 weeks) and intravenous administration of pertuzumab and trastuzumab (840 mg pertuzumab/8 mg/kg trastuzumab initial dose followed by 420 mg pertuzumab/6 mg/kg trastuzumab every 3 weeks). Trastuzumab is estimated to reach concentrations that are <1 mcg/mL by 7 months in at least 95% patients. Pertuzumab Cycle 7 C trough was 88.7 mcg/mL for PHESGO and 72.4 mcg/mL for intravenous pertuzumab with a geometric mean ratio (GMR) of 1.22 (90% CI: 1.14–1.31). Trastuzumab Cycle 7 C trough was 57.5 mcg/mL for PHESGO and 43.2 mcg/mL for intravenous trastuzumab with a GMR of 1.33 (90% CI: 1.24–1.43) [see Clinical Studies ] . Following subcutaneous administration of PHESGO , the pertuzumab median Cycle 7 C max was 34% lower and AUC 0-21days was 5% higher than that following intravenous administration of pertuzumab. The median trastuzumab Cycle 7 C max was 31% lower and AUC 0-21days was 10% higher, than that following intravenous administration of trastuzumab. Absorption The mean absolute bioavailability (CV%) was 0.71 (18%) for pertuzumab and 0.77 (13%) for trastuzumab after subcutaneous administration of the approved recommended dosage of PHESGO. The median time to reach Cmax was 3.8 days for both pertuzumab and trastuz