Zelboraf

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

Indications Zelboraf

The drug is indicated for the treatment of metastatic or inoperable forms of melanoma, in which case a BRAF V600 mutation must be found in its cells.

Release form

Available in tablets of 240 mg. One blister contains 8 tablets. The package contains 7 such blisters.

Pharmacodynamics

Vemurafenib is a small molecule inhibitor for internal use. It inhibits the active form of the enzyme BRAF kinases. Various mutations occurring in the BRAF gene provoke constitutive activation of the BRAF-type protein, as a result of which excessive signaling may occur along with cell proliferation in the absence of typical growth-inducing stimuli. As a potent, selective inhibitor of the BRAF-type oncogene, vemurafenib slows down signaling along the MAPK-associated pathway. Among the original BRAF substances, methyl ethyl ketone is considered the most studied.

Phosphorylation of this substance under the influence of BRAF creates an active form of pMEK, which then phosphorylates an extracellular command-controlled kinase of the ERK type. The resulting pERK passes into the nucleus, including transcriptional exciters that stimulate cell proliferation and their survival. Preclinical in vitro testing has demonstrated that the substance vemurafenib is a strong inhibitor of phosphorylation and activation of MEK forms together with ERK. This allows the drug to slow the proliferation of tumor cells that express proteins due to a BRAF V600 mutation.

Pharmacokinetics

The pharmacokinetics of vemurafenib were determined using a non-compartmental analysis - phases I and III of action were studied (20 patients who took the drug at a dose of 960 mg twice daily for 15 days, and 204 patients who took the drug for 22 days and reached a steady state during this period). The mean peak concentration and AUCo-hh were 60 μg/mL and 600 μg h/mL, respectively.

When vemurafenib is taken at a dosage of 960 mg twice daily (2 tablets of 240 mg), the peak concentration in the blood plasma is reached after approximately 4 hours. In the case of repeated use of the drug at this dosage, accumulation of the substance occurs, characterized by significant individual variability. Phase II testing showed that the average concentration values 4 hours after taking the drug increased from 3.6 μg/ml (day 1) to 49 μg/ml (day 15). Thus, the range was 5.4-118 μg/ml.

Food containing 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 values on a full stomach and on an empty stomach was 2.6 and 4.7, respectively. The peak concentration indicator increased from 4 to 8 hours when a single dose of the drug was taken with food.

At steady state (which occurs by day 15 in approximately 80% of patients), mean plasma drug levels of vemurafenib remain stable (pre-morning and 2-4 hour post-mortem dosing levels), as indicated by a mean ratio of 1.13. Considerable inter-individual variability was also observed in plasma drug levels at steady state, regardless of dose reduction.

The absorption rate after drug administration in patients with metastatic melanoma is 0.19 h'1 (with individual variability equal to 101%).

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

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

The clearance rate of vemurafenib in people with metastatic melanoma is 29.3 L/day (interindividual variability is 31.9%). The interindividual half-life values for vemurafenib are 56.9 h (range 5-95%: 29.8-119.5 h).

Dosing and administration

It is recommended to take 960 mg (4 tablets of 240 mg each) 2 times a day, so the daily dosage is 1920 mg. The drug should be taken in the morning and evening - the interval between doses should be approximately 12 hours. Each dose can be taken on an empty stomach or with food. The tablet should be swallowed whole, without crushing or chewing. Wash down with water.

Use of Zelboraf should be continued until symptoms of disease progression or unacceptable toxic effects of the drug appear.

If you miss a dose, you can take the dose a little later to maintain the regimen (2 times a day), but the interval between the missed and new doses should be at least 4 hours. You cannot take 2 doses at the same time. It is also not recommended to reduce the dosage of the drug to less than 480 mg 2 times a day.

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Use Zelboraf during pregnancy

Taking into account the mechanism of action of the drug, damage to the embryo may occur. However, the drug has not been tested on pregnant women. No signs of teratogenicity of Zelboraf were found during preclinical testing on rats.

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

Contraindications

Among the main contraindications:

• individual intolerance to vemurafenib, as well as other elements of the drug in the anamnesis;
• severe liver or kidney failure;
• lack of proper water-electrolyte balance (including magnesium), which cannot be corrected;
• SUIQT;
• before starting to take the drug, the corrected QT interval is >500 ms;
• use of drugs that provoke prolongation of the QT interval;
• lactation period;
• children and adolescents under 18 years of age (the safety and effectiveness of the drug has not been confirmed).

Side effects Zelboraf

The most common side effects are: severe fatigue, skin rashes, arthralgia, as well as photosensitivity, diarrhea, baldness, nausea, skin itching with papillomas. There were frequent cases of squamous cell carcinoma, which was usually removed surgically.

Tumors (benign or malignant or unspecified type), including polyps with cysts: most often this is the seborrheic form of keratosis; also, new-formed melanomas of the primary type and basalioma often occur; squamous cell carcinoma, located not on the skin, is occasionally observed.

Metabolism: Most commonly weight loss and loss of appetite.

Nerses: Mainly taste problems, headaches and polyneuropathy; dizziness and Bell's palsy are also common.

Visual organs: mainly uveitis; occasionally – retinal vein occlusion.

Vascular system: vasculitis is occasionally observed.

Respiratory system: cough is often observed.

Digestive organs: vomiting or constipation are very common symptoms.

Subcutaneous and cutaneous tissues: mainly papular and maculopapular rashes, actinic keratosis, dry skin, hyperkeratosis, sunburn, erythema, palmoplantar syndrome are observed; folliculitis, pilar keratosis, and panniculitis (including erythema nodosum) are also quite common manifestations; in some cases, Lyell's syndrome and malignant exudative erythema.

Musculoskeletal system: most often observed pain in the limbs, joints, muscles, back, and in addition to this, musculoskeletal pain and arthritis.

Allergy: intolerance reactions such as erythema, anaphylactic shock, generalized rash, decreased blood pressure may occur. If a severe intolerance reaction occurs, further use of Zelboraf should be discontinued.

Others: Frequent manifestations include fever, peripheral edema, and asthenic disorder.

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Overdose

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

In this case, it is necessary to stop taking the drug and instead conduct supportive treatment. In case of development of side effects, appropriate symptomatic therapy is carried out. It should be noted that there is no specific antidote for this drug.

Interactions with other drugs

Based on in vivo drug-drug interaction testing in patients with metastatic melanoma, vemurafenib was found to be a moderate CYP1A2 inhibitor and a CYP3A4 inducer.

As a result of combining the active component of Zelboraf with agents that have a short treatment interval and are metabolized with CYP1A2, as well as CYP3A4, their concentration indicators may change, so combining them is not recommended. If this is not possible, then it is necessary to preliminarily provide for a reduction in the dosage of the drug that is a CYP1A2 substrate.

Combination with vemurafenib increases the AUC of caffeine (a CYP1A2 substrate) by 2.6 times, while the AUC of midazolam (a CYP3A4 substrate) decreases by 39 percent with this combination. When combined with dextromethorphan (a CYP2D6 substrate) and its breakdown product (dextrophan), its AUC increased as a result of approximately 47% effect on the pharmacokinetics of dextromethorphan. It should be noted that it is not capable of being mediated by CYP2D6 inhibition.

As a result of combined administration with vemurafenib, an increase in the AUC of S-warfarin (a CYP2C9 substrate) by 18% is possible, therefore it is necessary to combine it with warfarin with caution, additionally monitoring INR values.

In vitro data indicate that vemurafenib is a CYP3A4 substrate and its concentration may be altered when co-administered with strong CYP3A4 inducers or inhibitors. Strong CYP3A4 inhibitors (such as ketoconazole with itraconazole, as well as clarithromycin, iephazadone and atazanavir, as well as saquinavir, ritonavir, nelifnavir and indinavir, as well as telithromycin and voriconazole) and CYP3A4 inducers (such as phenytoin with carbamazepine, rifabutin with rifampin, and rifapentine with phenobarbital) should be co-administered with caution.

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Storage conditions

The medicine should be kept in a place protected from sunlight, out of reach of children, and moisture. Temperature conditions – no more than 30°C.

Shelf life

Zelboraf is approved for use for 2 years from the date of manufacture of the drug.