Vectibix

Vectibix is an antineoplastic drug, a monoclonal antibody.

Indications Vectibix

It is used in the treatment of colorectal cancer that has metastases (mCRC) but does not have mutations (wild form) of the RAS type:

• often used as a combination therapy in the FOLFOX regimen;
• less commonly, it is used as a drug in the combination regimen FOLFIRI - in individuals who have received chemotherapy primarily that included a fluoropyrimidine (except irinotecan);
• as monotherapy in case of lack of results from treatment using chemotherapeutic regimens that use oxaliplatin and fluoropyrimidine with irinotecan.

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Release form

Released as a concentrate used in the manufacture of infusion solutions, in 5 ml vials. In a separate package - 1 vial with concentrate.

Pharmacodynamics

Panitumumab is a fully human (natural) IgG2 monoclonal antibody produced in a mammalian cell line (CHO) using recombinant DNA technology.

Panitumumab binds with strong affinity and specificity to human EGFR (skin growth factor) receptor. The EGFR receptor is a transmembrane glycoprotein that is part of the subfamily of type 1 tyrosine kinase terminal receptor, which includes EGFR (HER1/c-ErbB-1 factor) with HER2, and also HER3 with HER4. The EGFR receptor promotes cell growth within healthy epithelial tissues (including hair follicles and skin), and is also expressed in the area of most cellular neoplasms.

Panitumumab is synthesized with the ligand binding region of the EGFR receptor, resulting in a slowdown in the process of autophosphorylation of the terminal, which is provoked by all existing ligands of the EGFR receptor. Synthesis of the active component with the EGFR factor promotes internalization of the terminal, slowing down cell growth, inducing apoptosis, and also reducing the production of IL-8, as well as endothelial growth factor inside the vessels.

KRAS and NRAS genes are closely related to parts of RAS oncogene families. The above genes code for small processes synthesized with GTP protein (they participate in signal transmission processes). A number of irritants (including the EGFR receptor irritant) help activate KRAS with NRAS, and they, in turn, help stimulate the functions of other proteins located inside the cells, and also promote cell proliferation, as well as their survival and angiogenesis processes.

Activation of mutational processes within RAS-type genes is commonly observed in a variety of human tumors and also participates in tumor progression and oncogenesis.

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Pharmacokinetics

Used in monotherapy or in combination with chemotherapy, Vectibix has nonlinear pharmacokinetic parameters.

When a single dose of panitumumab was administered during a 1-hour infusion, the AUC level of the component increased even more than in accordance with the dosage, and its clearance rate, on the contrary, decreased - from 30.6 to 4.6 ml/day/kg (in the case of increasing the dosage from 0.75 to 9 mg/kg). However, when using dosages that exceed 2 mg/kg, the AUC level of the drug increases in accordance with the dose.

When the required dosage regimen was followed (6 mg/kg administered once over a 2-week period, in a 1-hour infusion), panitumumab values reached a steady-state value at the time of the 3rd infusion with the following values (± SD) for the maximum and minimum levels: 213±59 and 39±14 μg/ml, respectively. The values (± SD) for AUC0-tau together with CL were equal to 1306±374 and 4.9±1.4 ml/kg/day, respectively.

Half-life is about 7.5 days (in the period 3.6-10.9 days).

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Dosing and administration

Vectibix therapy should be administered under medical supervision by a physician experienced in antitumor therapy. Before starting therapy, it is necessary to determine that the RAS status is wild-type (such as KRAS or NRAS). The mutation status is determined in a specialized laboratory. A validated method for detecting the mutation type of KRAS (Exon 2, 3, and 4) or NRAS (Exon 2 or 3 or 4) is used.

The solution is administered by infusion, intravenously. An infusion pump is used, equipped with a special filter that passes through a permanent catheter or a peripheral type system of 0.2 or 0.22 μm, having a weak degree of synthesis with protein. It is recommended to carry out the infusion procedure for about 1 hour. If the patient tolerates the first procedure well, subsequent infusions are allowed with a duration of 0.5-1 hour. In this case, dosages that are more than 1000 mg must be administered with a duration of approximately 1.5 hours.

Before and after the administration procedure, it is necessary to rinse the infusion device using a sodium chloride solution to avoid mixing with other intravenous solutions or other drugs.

If adverse effects develop due to infusion, it may be necessary to reduce the rate of administration. It is prohibited to administer the drug intravenously by bolus or jet. Even if progression of the pathology has been detected, it is recommended to continue therapy.

Dosage regimens: the standard size is a single administration of 6 mg/kg for a 2-week period. The concentrate is diluted in a solution of sodium chloride (0.9%) - 9 mg/ml of the substance is required. In this case, it is necessary to obtain a final concentration that will not exceed 10 mg/ml.

In case of severe dermatological manifestations (grade 3 or higher), a dosage change may be required.

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Use Vectibix during pregnancy

There is insufficient information on the use of Vectibix in pregnant women. Animal tests have shown reproductive toxicity, but there is no information on a similar risk for humans. Given that EGFR receptors are involved in prenatal control and are an important part of healthy organogenesis and differentiation with proliferation of the developing fetus, it is believed that the drug may be unsafe for the child if used during pregnancy.

There is information that the human IgG element is able to penetrate the placenta, as a result of which the active substance of the drug can move to the developing fetus. Women of reproductive age are required to use contraception during the period of therapy with Vectibix, and then for at least 2 months after its completion. If pregnancy occurs during the period of therapy or when using the drug during gestation, it is necessary to warn the woman about the risk of miscarriage or a high probability of threat to the child.

There is no data on the passage of the active component into breast milk. Since the human IgG element is able to penetrate there, it is likely that panitumumab can too. The degree of absorption, as well as harm to the infant, are unknown. Breastfeeding is not recommended during therapy with the drug and for 2 months after its completion.

Vectibix may have negative effects on female fertility.

Contraindications

Main contraindications:

• a history of hypersensitivity (sometimes even life-threatening) to the active component or other additional elements of the drug;
• interstitial pneumonia or pneumofibrosis;
• use in chemotherapy regimens that contain the substance oxaleptin (for individuals with a mutated type of RAS mCRC or an unknown status of the RAS mCRC type);
• reception in childhood.

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Side effects Vectibix

Using the solution may cause the following side effects:

• invasive or infectious diseases: paronychia often occurs. Quite often, inflammatory processes also develop in the area of the urinary tract, in the tissue inside the subcutaneous layer, as well as in the hair follicles, as well as pustular rash and local infections. Occasionally, infections are observed on the eyelids and in the eyes;
• reactions of lymph and blood flow: anemia often appears, leukopenia develops more rarely;
• immune manifestations: hypersensitivity often develops, in rare cases signs of anaphylaxis are observed;
• metabolic disorders: anorexia, hypokalemia or hypomagnesemia often develop. Dehydration also occurs quite often, as well as hypocalcemia with hypophosphatemia and hyperglycemia;
• mental disorders: insomnia often appears, less often a feeling of anxiety is observed;
• disorders in the nervous system: dizziness or headaches often appear;
• problems with the visual organs: conjunctivitis often occurs. Less often, there is increased growth of eyelashes, as well as ocular hyperemia, irritation or itching in the eye area or dryness of the mucous membranes of the eye, as well as increased lacrimation and blepharitis. Rarely, irritation of the eyelids occurs, as well as keratitis. Ulcerative keratitis develops very rarely;
• cardiac dysfunction: tachycardia often appears, cyanosis is occasionally observed;
• disorders in the vascular system: DVT often occurs, hot flashes appear, and an increase or decrease in blood pressure is observed;
• manifestations from the mediastinum and sternum: cough or dyspnea often occurs. Nosebleeds and pulmonary embolism also often occur. Dryness of the nasal mucosa and bronchial spasms occasionally develop. Interstitial pathology may occur;
• Gastrointestinal dysfunction: nausea, constipation, vomiting, diarrhea, as well as stomatitis and abdominal pain are often observed. Dyspeptic symptoms, GERD, dry mouth, bleeding from the anus and cheilosis are quite common. Cracked lips or dry lips are rarely observed;
• reactions of the subcutaneous layer and skin: rash, alopecia, erythema, acne-like dermatitis often appear, as well as dry skin, itching, acne and cracks in the skin. Skin ulcers, dermatitis, hypertrichosis with onychoclasis often occur, as well as scabs, increased sweating, nail problems and palmar-plantar syndrome. Quincke's edema, ingrown nails, onycholysis and hirsutism are rarely observed. Lyell's or Stevens-Johnson syndrome develops isolatedly, as well as necrosis of the skin;
• disorders of the musculoskeletal system and connective tissues: often there is pain in the back, less often – pain in the limbs;
• systemic disorders and problems at the injection site: asthenia or hyperthermia, increased fatigue, peripheral edema and inflammation in the mucous membrane area often occur. Pain (including in the sternum) and chills occur quite often. Systemic reactions to the infusion are rarely observed;
• test results: weight loss often occurs. Less commonly, magnesium levels decrease.

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Overdose

During clinical tests, doses of no more than 9 mg/kg of the drug (inclusive) were tested. Cases of overdose were identified when the required medicinal dose (6 mg/kg) was exceeded by 2 times – up to 12 mg/kg. Adverse effects correspond to the existing safety profile in the standard dosage and are observed in the form of symptoms from the skin, as well as exsicosis, diarrhea and a feeling of weakness.

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Interactions with other drugs

Interaction testing of Vectibix with irinotecan in people with mCRC showed that the pharmacokinetic properties of irinotecan with its active degradation product SN-38 were not altered. A cross-over comparative test showed that irinotecan (like IFL or FOLFIRI) did not affect the properties of panitumumab.

The combination of the drug, IFL or bevacizumab with chemotherapy is not recommended. An increase in fatal outcomes has been observed with such combinations.

Vectibix should not be used concomitantly with chemotherapy that includes oxaliplatin in patients with metastatic colorectal cancer in which the tumor has a RAS mCRC gene with mutation elements or with an unknown status of the RAS mCRC gene. Progression-free survival and overall survival studies have been conducted in patients with a mutated RAS type who received Vectibix or used a FOLFOX-type chemotherapy regimen.

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Storage conditions

Vectibix should be kept out of reach of small children at a temperature of 2-8°C, without freezing the medicine. The prepared solution can be stored for a maximum of 24 hours at a temperature of 2-8°C.

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Shelf life

Vectibix is approved for use for a period of 3 years from the date of manufacture of the medicine.

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