Vectibix

Vectibix is an antineoplastic drug, a monoclonal antibody.

Indications of the vectibix

It is used in the treatment of rectal cancer, against which metastasis (mCRC) is observed, but there are no mutations (wild form) such as RAS:

• often used as a means of combined treatment in the FOLFOX scheme;
• less often it is used as a drug in the combined FOLFIRI scheme - in people who received chemotherapy first, at which fluoropyrimidine was used (except irinotecan);
• as monotherapy in the absence of the result of treatment with the use of chemotherapeutic schemes in which oxaliplatin and fluoropyrimidine with irinotecan are used.

[1], [2]

Release form

Release in the form of a concentrate used in the manufacture of infusion solutions, in flacons with a volume of 5 ml. In a separate package - 1 bottle with concentrate.

Pharmacodynamics

Panitumumab is a complete human (natural) monoclonal antibody of the IgG2 type, which is produced inside the mammalian cell line (CHO) using recombinant DNA technology.

Panitumumab with a strong affinity, as well as specificity, is synthesized with human endings of EGFR (skin growth factor). The EGFR receptor is a glycoprotein of the transmembrane form, which is part of the subfamily of type 1 of the tyrosine kinase terminus, which includes both EGFR (HER1 / c-ErbB-1 factor) and HER2, and HER3 plus HER4. The EGFR receptor helps the cell growth inside healthy epithelial tissues (this includes the hair follicles and the skin), and is also expressed in the field of most cellular neoplasms.

The synthesis of panitumumab occurs with the ligand binding region of the EGFR receptor, which slows down the endophosphate autophosphorylation process, which is provoked by all the existing EGFR receptor ligands. Synthesis of the active ingredient with the EGFR factor facilitates the internalization of the end, inhibits cell growth, induces apoptosis, and in addition reduces the production of IL-8, as well as a growth factor of the endothelial type within the vessels.

KRAS type genes, as well as NRAS, have a close relationship with parts of the RAS family of oncogenes. The above genes encode small processes synthesized with GTP-protein (they participate in signal transduction processes). A number of irritant substances (including the EGFR receptor stimulus) help activation of KRAS with NRAS, and they in turn help stimulate the functions of other proteins located inside the cells, and also promote cellular reproduction, as well as their survival and processes angiogenesis.

Activation of mutational processes inside genes like RAS is usually carried out in a variety of human tumors, and in addition participates in the progression of neoplasm and oncogenesis.

[3], [4], [5], [6], [7], [8], [9]

Pharmacokinetics

Used in monotherapy or combined with chemotherapy, Vectibix has non-linear pharmacokinetic parameters.

With the introduction of a one-time dose of panitumumab during the last 1 hour of 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 a value of 30.6 to an index of 4.6 ml / day / kg (in the case of an increase dosages from 0.75 to 9 mg / kg). But when dosages that exceed 2 mg / kg are used, the drug AUC level rises according to the dose.

In the case of compliance with the required dosage regimen (administration of 6 mg / kg once per 2 weeks, in an infusion of 1 hour duration), panitumumab values reached a steady value at the time of the 3rd infusion with the following (± SD) numbers of the maximum and minimum level: 213 ± 59, respectively, and 39 ± 14 μg / ml, respectively. The values (± SD) of AUC0-tau together with CL were 1306 ± 374, respectively, and 4.9 ± 1.4 ml / kg / day, respectively.

The half-life is about 7.5 days (in the period of 3.6-10.9 days).

[10], [11], [12], [13]

Use of the vectibix during pregnancy

There is not enough information about the use of Vectibix pregnant. During animal tests, the presence of toxic effects on reproductive function was found, but there is no information about a similar risk for a person. Given that EGFR receptors are participants in control during prenatal development, and are an important part of healthy organogenesis processes, and in addition differentiation with proliferation of the developing fetus, it is believed that the drug may be unsafe for the child if it is used during pregnancy.

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

There is no data on the passage of the active ingredient into the mother's milk. Because the human IgG element is able to penetrate there, it is likely that panitumumab can also. The degree of absorption, as well as harm to the baby is not known. It is not recommended to breastfeed during the period of therapy with the drug and in the period of 2 months after its completion.

Vektibiks can have a negative effect on female fertility.

Contraindications

The main contraindications:

• the existing history of hypersensitivity (sometimes even life-threatening) with respect to the active component or other additional elements of the drug;
• interstitial form of pneumonia or pneumofibrosis;
• use in chemotherapeutic regimens that contain the substance oxaliptin (for individuals with a mutated type of RAS mCRC or an unknown status such as RAS mCRC);
• admission in childhood.

[14], [15], [16]

Side effects of the vectibix

Use of the solution may cause the following side effects:

• invasive or infectious diseases: often there is a paronychia. Enough often also develop inflammation in the urinary duct, in the fiber inside the subcutaneous layer, as well as in the hair follicles, and in addition, pustular rashes and local infections. Occasionally there are infections on the eyelids and in the eyes;
• lymphatic and blood flow reactions: anemia often occurs, leukopenia is more rare;
• immune manifestations: often there is increased sensitivity, in rare cases, signs of anaphylaxis are observed;
• disturbance of metabolic processes: often develops anorexia, hypokalemia or hypomagnesemia. Dehydration often occurs, but hypocalcemia with hypophosphatemia and hyperglycaemia;
• mental disorders: often there is an insomnia, less often there is a feeling of anxiety;
• disorders in the NA: often there are dizziness or headaches;
• problems with the visual organs: often there is conjunctivitis. Less frequent is increased lash growth, and in addition, eye hyperemia, irritation or itching in the eye area, or dryness of the eye mucous membranes, as well as increased lacrimation and blepharitis. Occasionally there is irritation of the eyelids, as well as keratitis. Quite rarely develops the ulcerative form of keratitis;
• disturbances of cardiac function: often there is a tachycardia, occasionally there is a cyanosis;
• disorders in the vascular system: often there is GWT, there are tides, and there is an increase or decrease in blood pressure;
• manifestations of the mediastinum and sternum: often there is a cough or dyspnea. Also, bleeding from the nose often develops and PE develops. Occasionally, dryness of the nasal mucosa and bronchial spasms develop. The appearance of interstitial pathology is possible;
• disorders of the gastrointestinal tract: often there is the appearance of nausea, constipation, vomiting, diarrhea, and in addition stomatitis and abdominal pain. Quite often there are dyspeptic phenomena, GERD, dryness of the oral mucosa, bleeding from the anus and cheilosis. Rarely observed cracked lips or their dryness;
• reactions of the subcutaneous layer and skin: often there is a rash, alopecia, erythema, similar to acne dermatitis, and besides skin dryness, itching, acne and cracks in the skin. Often there is an ulcer on the skin, dermatitis, hypertrichosis with onychocussia, and in addition, scab, increased sweating, problems with nails and palmar-plantar syndrome. Occasionally observed edema Quincke, ingrowth of nail plates, onycholysis and hirsutism. The Lyell or Stevens-Johnson syndrome develops singly, and in addition the necrosis of the skin;
• disorders of the function of ODA and connective tissue: often there are pain in the back, less often - pain in the limbs;
• systemic disorders and problems at the site of administration: often there is asthenia or hyperthermia, increased fatigue, peripheral puffiness and inflammation in the mucosa. Quite often there are pains (including those in the sternum) and chills. Occasionally there are systemic reactions to the introduction of infusion;
• test data: often weight loss occurs. A decrease in the magnesium level is observed more rarely.

[17], [18], [19], [20]

Dosing and administration

To conduct therapy with Vectibix is necessary under medical supervision, and the specialist should have experience of antitumor treatment. Before it starts, you need to determine that the RAS status has a wild type (such as KRAS or NRAS). The determination of the mutational status is performed in a laboratory of a specialized type. This uses a validated method of detection of the mutational type KRAS (Exxon 2, 3, and 4) or NRAS (Exxon form 2 or 3 or 4).

The solution is administered by infusion, intravenously. This uses an infusion pump equipped with a special filter that passes through a permanent catheter or a peripheral type system of 0.2 or 0.22 microns, having a weak degree of synthesis with the protein. It is recommended to carry out the infusion procedure for about 1 hour. If the patient is well tolerated, the first procedure is allowed to make subsequent infusions with a duration of 0.5-1 hour. Dosages of more than 1000 mg should be administered with a duration of approximately 1.5 hours.

Before and after the procedure, the infusion device should be rinsed using a solution of sodium chloride - to avoid mixing with other intravenous solutions or other drugs.

With the development of negative manifestations due to infusion, a reduction in the rate of administration may be necessary. It is forbidden to inject the drug intravenously or bolusily. Even if the progression of the pathology has been identified, it is recommended to continue therapy.

Dosage regimens: The standard size is a single dose 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. It is necessary to obtain a final concentration that does not exceed 10 mg / ml.

In severe dermatological manifestations (grade 3 or more), dosage changes may be necessary.

[21], [22], [23], [24]

Overdose

In clinical tests, a dose of not more than 9 mg / kg of the drug was included (inclusive). Overdose cases were detected in excess of the required dosage dose (6 mg / kg) 2 times - up to 12 mg / kg. Negative manifestations correspond to the existing safety profile in the standard dosage and are observed in the form of symptoms from the side of the skin, as well as in the form of exsicosis, diarrhea and sensation of weakness.

[25], [26], [27]

Interactions with other drugs

Interaction tests using Vectibix with irinotecan in humans with mCRC demonstrated that the pharmacokinetic characteristics of irinotecan with its active SN-38 disintegration product did not change in this case. A comparative cross-sectional test revealed that the substance irinotecan (such as IFL or FOLFIRI) does not have an effect on the properties of panitumumab.

The combination of a drug, IFL, or bevacizumab substance with chemotherapy procedures is not recommended. With such combinations, there was an increase in the number of deaths.

It is forbidden to apply Vectibix simultaneously with chemotherapy, in the scheme of which there is an oxaliplatin component - to people with rectal cancer (with metastases), in which the tumor has a gene of the RAS type mCRC with mutation elements or with unknown status of the RAS mCRC neoplasm gene. Studies of short survival without determining the progression of the disease, as well as the duration of overall survival, were performed in persons with a mutated type of RAS who received Vectibix, or who used a chemotherapeutic regimen such as FOLFOX.

[28], [29], [30], [31]

Storage conditions

Vectibix is required to be kept out of reach of young children, at a temperature of 2-8 ° C, without freezing the medicine. The finished solution can be stored for a maximum of 24 hours under temperature conditions within 2-8 ° C.

[32]

Shelf life

Vectibix is allowed to be used in the period of 3 years from the date of manufacture of the medicine.

[33], [34]