Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermal growth factor receptor (EGFR).
EGFR signalling pathways are involved in the control of cell survival, cell cycle progression, angiogenesis, cell migration and cellular invasion/metastasis.
Cetuximab binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition of the function of the receptor. It further induces the internalisation of EGFR, which can lead to down-regulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-expressing tumour cells (antibody dependent cell-mediated cytotoxicity, ADCC).
Cetuximab does not bind to other receptors belonging to the HER family.
The protein product of the proto-oncogene RAS (rat sarcoma) is a central down-stream signal- transducer of EGFR. In tumours, activation of RAS by EGFR contributes to EGFR-mediated increased proliferation, survival and the production of pro-angiogenic factors.
RAS is one of the most frequently activated family of oncogenes in human cancers. Mutations of RAS genes at certain hot-spots on exons 2, 3 and 4 result in constitutive activation of RAS proteins independently of EGFR signalling.
In both in vitro and in vivo assays, cetuximab inhibits the proliferation and induces apoptosis of human tumour cells that express EGFR. In vitro cetuximab inhibits the production of angiogenic factors by tumour cells and blocks endothelial cell migration. In vivo cetuximab inhibits expression of angiogenic factors by tumour cells and causes a reduction in tumour neo-vascularisation and metastasis.
In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to improve anti-tumour efficacy in non-clinical models.
Cetuximab pharmacokinetics were studied when cetuximab was administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy in clinical studies. Intravenous infusions of cetuximab exhibited dose-dependent pharmacokinetics at weekly doses ranging from 5 to 500 mg/m² body surface area.
When cetuximab was administered at an initial dose of 400 mg/m² body surface area, the mean volume of distribution was approximately equivalent to the vascular space (2.9 L/m² with a range of 1.5 to 6.2 L/m²). The mean Cmax (± standard deviation) was 185±55 microgram per mL. The mean clearance was 0.022 L/h per m² body surface area. Cetuximab has a long elimination half-life with values ranging from 70 to 100 hours.
When cetuximab was administered in a weekly dose regimen (400 mg/m² loading dose followed by 250 mg/m² weekly dose), cetuximab serum concentrations reached stable levels after three weeks of cetuximab monotherapy. Mean peak cetuximab concentrations were 155.8 microgram per mL in week 3 and 151.6 microgram per mL in week 8, whereas the corresponding mean trough concentrations were 41.3 and 55.4 microgram per mL, respectively. In a study of cetuximab administered in combination with irinotecan, the mean cetuximab trough levels were 50.0 microgram per mL in week 12 and 49.4 microgram per mL in week 36.
When cetuximab was administered in a biweekly dose regimen (500 mg/m² every other week), serum concentrations reached stable levels after five weeks of cetuximab monotherapy. Mean peak cetuximab concentration was 297 microgram per mL in week 5, the corresponding mean trough concentration was 31.0 microgram per mL.
Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve the biodegradation of the antibody to smaller molecules, i.e. small peptides or amino acids.
Population pharmacokinetic analyses showed that there were no clinically relevant effects of race, age, sex, renal or hepatic status on the pharmacokinetic characteristics of cetuximab. A relationship was observed between gender and drug exposure, with higher exposure in females, this was however not considered clinically relevant.
Based on a population pharmacokinetic analysis, mild (CRCL ≥60 and <90 mL/min) and moderate (CRCL ≥30 and <60 mL/min) renal impairment had no clinically meaningful effect on cetuximab pharmacokinetics compared to subjects with normal (CRCL ≥90 mL/min) renal function. No dose adjustment is recommended for patients with mild or moderate renal impairment. The pharmacokinetics of cetuximab in patients with severe (CRCL ≥15 and <30 mL/min) renal impairment or end-stage renal disease have not been evaluated.
Based on a population pharmacokinetic analysis, mild hepatic impairment, as defined by NCI-ODWG, had no clinically meaningful effect on cetuximab pharmacokinetics compared to subjects with normal hepatic function. No dose adjustment is recommended for patients with mild hepatic impairment. The effect of moderate or severe hepatic impairment, as defined by NCI-ODWG criteria, on cetuximab pharmacokinetics has not been assessed.
In a phase-I study in paediatric patients (1-18 years) with refractory solid tumours, cetuximab was administered in combination with irinotecan. The pharmacokinetic results were comparable to those in adults.
Dose-dependent skin alterations, starting at dose levels equivalent to those used in humans, were the major findings observed in toxicity studies with Cynomolgus monkeys (a chronic repeat-dose toxicity study and an embryo-foetal development study).
An embryo-foetal toxicity study in Cynomolgus monkeys revealed no signs of teratogenicity. However, dependent on the dose, an increased incidence of abortion was observed.
Non-clinical data on genotoxicity and local tolerance including accidental administration by routes other than the intended infusion revealed no special hazard for humans.
No formal animal studies have been performed to establish the carcinogenic potential of cetuximab or to determine its effects on male and female fertility.
Toxicity studies with co-administration of cetuximab and chemotherapeutic agents have not been performed.
No non-clinical data on the effect of cetuximab on wound healing are available to date. However, in preclinical wound healing models EGFR selective tyrosine kinase inhibitors were shown to retard wound healing.
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