Zelborough

The drug Zelboraf is a small molecule of internal use, and in addition it is a kinase inhibitor.

Indications Zelborough

The drug is indicated for the elimination of metastatic or inoperable forms of melanoma, while a mutation of the BRAF V600 type should be found in its cells.

Release form

It is produced in tablets with a volume of 240 mg. One blister plate contains 8 tablets. The package contains 7 such blisters.

Pharmacodynamics

Vemurafenib is a low molecular weight inhibitor of internal use. It suppresses the active form of the enzyme BRAF-kinases. The various mutations in the BRAF gene provoke a constitutive activation of the activity of the BRAF-type protein, as a result of which excessive signaling can occur with the multiplication of cells, although there are no typical causative agents that cause growth. Being a potent selective inhibitor of the oncogene of the BRAF type, the vemurafenib substance slows the signaling along the pathway connected to the MAPK. Among the BRAF starting materials, the most studied is methyl ethyl ketone.

Phosphorylation of this substance under the influence of BRAF creates an active form of PMEC, and it further phosphorylates the extracellular kinase-driven kinase type ERK. The pERK formed as a result of this process passes into the nucleus, including transcriptional pathogens that stimulate cellular reproduction and their survival. Preclinical in vitro tests demonstrated that the substance of vemurafenib is a potent inhibitor of phosphorylation, as well as the activation of MEK forms along with ERK. This allows the drug to slow down the multiplication of tumor cells, which, because of the BRAF V600 mutation, express proteins.

Pharmacokinetics

The pharmacokinetics of vemurafenib substance were determined with the help of a non-compartmental analysis - the I and III phases of action were investigated (20 patients who used the drug at a dose of 960 mg twice a day for 15 days, and 204 patients taking the drug for 22 days and reached the equilibrium state for this period). The mean peak concentration and AUCo-hh are 60 μg / ml, respectively, and 600 μg / ml, respectively.

When vemurafenib is used at a dosage of 960 mg 2 r. / Day. (2 tablets with a volume of 240 mg) peak concentration in the blood plasma reaches about 4 hours. In case of multiple use of the drug in this dosage, there is accumulation of a substance characterized by a noticeable individual variability. Phase II testing showed that the average concentration after 4 hours after the use of drugs increased from 3.6 μg / ml (1 day) to 49 μg / ml (day 15). Thus, the range was 5.4-118 μg / ml.

Food that contains a large amount of fat increases the relative bioavailability of a single dose of the substance (960 mg). The difference between the peak concentration and AUC for the full stomach and fasting was 2.6 and 4.7, respectively. The peak concentration was increased from 4 to 8 hours, when a single dose of medicine was consumed with food.

In an equilibrium state (which occurs on the 15th day in about 80% of patients), the average level of vemurafenib in the blood plasma remains stable (concentration level before the use of the morning dosage and after 2-4 hours) - this is seen from the average ratio, 1.13. Noticeable individual variability was also noted with respect to the drug content in the blood plasma in an equilibrium state, regardless of the dose reduction.

The rate of absorption after drug use in patients with a metastatic form of melanoma is 0.19 h-1 (individual variation is 101%).

The volume of distribution of the active substance in patients with a metastatic form of melanoma is 91 liters (individual variability is 64.8%). The drug binds well to plasma proteins in vitro (more than 99%).

95% (average) dosage of the drug is excreted from the body for 18 days. About 94% is excreted together with feces, and even less than 1% of the drug is excreted in the urine. Because CYP3A4 is the primary enzyme that is responsible for the process of active substance exchange in vitro, the degradation products of conjugation (glucuronidation together with glycosylation) are also observed in patients. However, in the blood plasma the drug remains largely unchanged (95%). Although metabolic processes do not contribute to the formation of the required amount of degradation products in plasma, the importance of metabolism for the excretion process can not be excluded.

The coefficient of purification of vemurafenib in people with a metastatic form of melanoma is 29.3 l / day. (individual variability is 31.9%). The indices of the individual half-lives of vemurafenib are 56.9 hours (the difference between 5-95% is 29.8-119.5 h).

Dosing and administration

It is recommended to use 960 mg (4 tablets with a volume of 240 mg) 2 r / day, so the daily dosage is 1920 mg. Use the drug is required in the mornings and evenings - the interval between doses should be approximately 12 h. Each dose can be used on an empty stomach or with food. Swallow the tablet completely, without crushing or chewing. Wash down with water.

The use of Zelboraf should be continued until symptoms of disease progression or an unacceptable toxic effect of the drug appear.

If you skip the next dose, you can take this dose a little later to maintain the regimen (2 r./day), but the gap between the missed and the new doses should be at least 4 hours. Do not take 2 doses at the same time. Also, it is not recommended to lower the dosage of the drug to less than 480 mg 2 r. / Day.

[2]

Use Zelborough during pregnancy

If you take into account the mechanism of action of drugs, damage to the embryo can occur. But there was no testing for pregnant women. In the process of preclinical testing in rats, the signs of teratogenicity of Zelboraf were not found.

Therefore, Zelboraf is recommended to be taken only when from its use the risks to the fetus are lower than the benefits for the woman. Men and women in reproductive age should use reliable contraception during the entire treatment course, as well as at least six months after its termination.

Contraindications

Among the main contraindications:

• individual intolerance to vemurafenib, as well as other elements of medicines in the anamnesis;
• severe form of hepatic or renal insufficiency;
• lack of the correct water-electrolyte exchange (including magnesium), which can not be corrected;
• SUIQT;
• before the start of the drug use, the QT interval is> 500 ms;
• the use of drugs, which provoke the elongation of the values of the interval QT;
• lactation period;
• children with adolescents under 18 years of age (the safety and efficacy of the drug has not been confirmed).

Side effects Zelborough

Most of the side effects occur: severe fatigue, rashes on the skin, arthralgia, as well as photosensitivity, diarrhea, baldness, nausea, pruritus with papillomas. Often there were cases of squamous cell carcinoma, which was usually eliminated by surgery.

Tumors (benign or malignant or unspecified type), including polyps with cysts: most often it is the seborrheic form of keratosis; often new melanomas of the primary type and basal cell develop; squamous cell carcinoma occurs occasionally, not on the skin.

Metabolism: most often weight loss and appetite.

The organs of the National Assembly: basically - problems with taste perception, headaches and polyneuropathy; also dizziness and Bell's paralysis are common.

Visual organs: mostly uveitis; Occasionally - blockage of retinal veins.

Vascular system: occasionally observed vasculitis.

Respiratory system: Cough is often observed.

Organs of digestion: very frequent symptoms are vomiting or constipation.

Subcutaneous and dermal tissues: mainly papular and maculopapular rashes, actinic form of keratosis, cutaneous dryness, hyperkeratosis, sunburn, erythema, palmar-plantar syndrome; also quite frequent manifestations are folliculitis, pilar keratosis, and in addition to panniculitis (including erythema nodosa); in some cases - Lyell's syndrome and malignant exudative erythema.

Musculoskeletal system: most often there are painful sensations in the limbs, joints, muscles, back, and in addition musculoskeletal pain and arthritis.

Allergy: such reactions of intolerance as erythema, anaphylactic shock, generalized rash, lowering of blood pressure can be observed. If there is a severe reaction of intolerance, Zerboraf should be discontinued.

Other: frequent manifestations are fever, peripheral puffiness, as well as asthenic disorder.

[1]

Overdose

Signs of an overdose are itching and rashes on the skin, as well as increased fatigue.

In such a case, it is necessary to cancel the use of the medication and, instead, to provide supportive treatment. In case of side effects, appropriate symptomatic therapy is performed. It should be noted that there is no specific antidote for this drug.

Interactions with other drugs

According to in vivo testing for interaction with other drugs (in patients with a metastatic form of melanoma) it was found that vemurafenib is a moderately active inhibitor of the CYP1A2 category, as well as an inducer of the CYP3A4 category.

As a result of the combination of the active component of Zelboraf with agents having a short healing interval and metabolized with CYP1A2, as well as CYP3A4, their concentration can vary, so it is not recommended to combine them. If this is not possible, then a reduction in the dosage of the preparation, which is the substrate of CYP1A2, should be provided in advance.

The combination with vemurafenib raises 2.6 times the AUC value of caffeine (it is a substrate of the CYP1A2 type), but the midpoint of the midazolam AUC (this is the substrate of the CYP3A4 type) is reduced by 39 percent. When combined with dextromethorphan (a substrate like CYP2D6), as well as its decay product (dextrofan), its AUC increased as a result of approximately 47% of the effect on the pharmacokinetics of dextromethorphan. It should be noted that it is not capable of being mediated by the suppression of CYP2D6.

As a result of a combination with vemurafenib, AUC S-warfarin (a substrate of the type CYP2C9) can be increased by 18%, so it is necessary to combine it with warfarin carefully, additionally monitoring the indices of MNO.

The information obtained from the in vitro study revealed that vemurafenib is a substrate of the CYP3A4 type, so that in combination with strong inducers or inhibitors of the CYP3A4 types, a change in its concentration is possible. Highly potent CYP3A4 inhibitors (such as ketoconazole with itraconazole, as well as clarithromycin, isfazadone and atazanavir, and besides this, saquinavir, ritonavir, nelfonavir and indinavir, and with them telithromycin and voriconazole), as well as inducers such as CYP3A4 (such as phenytoin with carbamazepine, rifabutin with rifampin, and rifapentin with phenobarbital) should be used cautiously at the same time as vemurafenib.

[3], [4]

Storage conditions

Keep the medicine in a place that is closed from sunlight, to access children, as well as moisture. Temperature conditions - no more than 30 ° С.

Shelf life

Zelboraf is allowed to be used for 2 years from the date of manufacture of the medicine.