The mechanism of action
vemurafenib is an inhibitor of serine-threonine kinase encoding gene BRAF (v-raf murine sarcoma viral oncogene homolog B1). As a result of mutations in the BRAF gene occurs constitutively activated oncogenic BRAF protein and, consequently, cell proliferation in the absence of growth factors.
According to research conducted by biochemical vemurafenib is a potent inhibitor of BRAF-activating kinases with mutations at codon 600.
This inhibitory effect was confirmed during the phosphorylation reaction extracellular signal-regulating kinases and cell antiproliferation available in melanoma cell lines expressing the BRAF gene with mutations V600. In tests antiproliferation cell lines with V600 mutations (V600E line, V600R, V600D and V600K) the concentration of half-maximal inhibition (IC50) ranged from 0.016 to 1.131 mol, while the IC50 for cell lines with the “wild” type BRAF gene was 12.06 and 14.32 mol, respectively.
vemurafenib – a substance with low solubility and low permeability (class 4 according to Biopharmaceutics Classification System). Pharmacokinetic parameters were estimated by vemurafenib nekompartmentnogo analysis and using a population pharmacokinetic analysis. Pharmacokinetics vemurafenib is dose dependent within the dose range of 240 to 960 mg when 2 times per day. Linear pharmacokinetics are also confirmed by the population pharmacokinetic analysis.
The absolute bioavailability vemurafenib 240 mg tablet is unknown. When receiving vemurafenib in a single dose of 960 mg (4 tablets of 240 mg) median time to reach maximum plasma concentration (Tmax) is approximately 4 h. Repeated reception vemurafenib at a dose of 960 mg twice daily observed accumulation of the drug, which is characterized by high interindividual variability. Average of area under the curve “concentration-time” AUC0-8ch and maximum plasma concentration (Cmax) (± standard deviation) in 1 day totaled 22.1 ± 12.7 pg * hr / mL and 4.1 ± 2.3 mcg / mL, respectively. During analysis nekompartmentnogo vemurafenib when receiving a dose of 960 mg twice daily for 15 hours AUC increased 15-17 times compared to the AUC in 1 day, Cmax on day 15 increased 13-14 times compared to the Cmax in 1 day . In the equilibrium state AUC0-8ch and Cmax reached 380.2 ± 143.6 ug * h / mL and 56.7 ± 21.8 pg / ml, respectively.
Foods rich in fat increases vemurafenib exposure after a single application in a dose of 960 mg. Geometric mean Cmax and AUC parameters increased when receiving vemurafenib with food as compared with the fasted 2.5 and from 4.6 to 5.1 times, respectively. Median Tmax was increased from 7.5 hours to 4 hours at a single dose of vemurafenib with food. Data on the effect of food intake on vemurafenib exposure is not in an equilibrium state. Continuous Reception vemurafenib fasting may lead to significant reduction in exposure vemurafenib in the equilibrium state compared with the reception vemurafenib with food or shortly before a meal. It is expected that the irregular reception vemurafenib vemurafenib fasting exposure is in the equilibrium state will change slightly because of the high degree of accumulation vemurafenib at equilibrium. Safety and efficacy of vemurafenib in basic research have been studied in patients treated with vemurafenib as a food, and apart from meals.
You can change the vemurafenib exposure depending on the composition, volume and acidity (pH) of the fluid of the gastrointestinal tract motility and transit time of food, the composition of bile.
In the equilibrium state (attained at 15 hours 80% of patients), the average exposure vemurafenib plasma is stable over 24 hours, as evidenced by an average ratio of the plasma concentration before and 2-4 hours after the morning dose, equal to 1.13.
After oral absorption rate constant in patients with metastatic melanoma of 0.19 h-1 (interindividual variability is 101%).
According population analysis vemurafenib apparent volume of distribution in patients with metastatic melanoma is 91 liters (interindividual variability was 64.8%). Vemurafenib characterized by high in vitro binding to human plasma proteins (99%).
isozyme cytochrome P450 (CYP) 3A4 – primary enzyme involved in the metabolism of vemurafenib in vitro. The man also found product conjugation with glucuronic acid and glycosylation products. Value vemurafenib and its metabolites were studied in a clinical study material balance after a single dose vemurafenib with 14C-radiolabeled. The blood plasma preparation contained mainly unchanged (> 95%), whereas metabolites constitute ≤5%
According population analysis apparent clearance vemurafenib in patients with metastatic melanoma is 29.3 L / day (interindividual variability is 31.9%), median half-life vemurafenib is 51.6 hours (individual range of values between the 5th and 95th percentile is 29.8 -119.5 hours).
According to the study of the material balance, on average 95% of the dose appears vemurafenib for 18 days. Most (94%) vemurafenib unchanged and its metabolites derived intestine, less than 1% – kidneys. Excretion of the drug unchanged in bile may be an important route of excretion. However, since the absolute bioavailability of the drug is unknown, the value of the influence hepatic and renal excretion on the clearance of the drug in an unchanged form also can not be estimated. Vemurafenib is a substrate and inhibitor of P-glycoprotein in vitro.
Pharmacokinetics in special patient groups
According to the results of a population pharmacokinetic analysis of patient age has no statistically significant effect on the pharmacokinetic parameters of vemurafenib.
According to the results of a population pharmacokinetic analysis in men the apparent clearance of the drug more than 17%, and the apparent volume of distribution – 48% compared to women. In this case, the differences in exposure vemurafenib relatively small, indicating that there is no need to adjust the dose depending on the patient’s sex, body mass index or body weight.
Patients childhood and adolescents
Research pharmacokinetics of vemurafenib in pediatric patients and adolescents have not been conducted.
Patients with impaired renal function
According to a population pharmacokinetic analysis of patients with metastatic melanoma mild and moderate renal impairment (creatinine clearance > 40 ml / min) did not affect the apparent clearance vemurafenib. Clinical data and pharmacokinetic data in patients with severe renal impairment is insufficient to determine the need for dose adjustment.
Patients with hepatic impairment
vemurafenib predominantly excreted in the bile. According to a population pharmacokinetic analysis of patients with metastatic melanoma increasing activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to a value of 3 times the upper limit of normal, no effect on the apparent clearance vemurafenib. Clinical data and data on the pharmacokinetics in patients with severe hepatic impairment is insufficient to determine the effect of metabolic disorders or excretory hepatic function on the pharmacokinetics of vemurafenib.
F.Hoffmann-La Roche Ltd, Switzerland
Active substance: 240 mg vemurafenib;
Excipients: anhydrous colloidal silica – 10.4 mg Croscarmellose sodium – 29.4 mg, giproloza (hydroxypropyl) – 4.25 mg magnesium stearate – 5.95 mg
unresectable or metastatic melanoma with BRAF V600 mutation in adult patients as monotherapy.
- Increased sensitivity to vemurafenib and the other components of the drug in history.
- Pregnancy and breastfeeding.
- Children under
- Not measurable correcting violations of water-electrolyte balance (including magnesium balance) of the elongated slot QT syndrome medication, facilitate lengthening of the interval QT, corrected interval QT (QTc) > 500 ms before therapy
- Severe renal and liver failure.
18 years (effectiveness and safety have not been established).
- Simultaneous treatment with warfarin, potent inhibitors and inducers isoenzyme CYP3A4, glyukuronirovaniya and / or transport proteins (including P-glycoprotein), drugs that are substrates isoenzyme CYP1A2. Care must be taken when used together vemurafenib and CYP2C8 isozyme substrates with a narrow therapeutic range (see. See “The interaction with other drugs»).
Benign, malignant and unspecified tumors (including cysts and polyps): very often – squamous cell carcinoma of the skin, seborrheic keratosis, skin papilloma; often – basal cell carcinoma, the new primary melanoma; infrequently – squamous cell carcinoma nekozhnoy localization
From a metabolism: often – decreased appetite, weight loss
From the nervous system: very often – headache, dysgeusia (distortion of taste perception), peripheral neuropathy; often – facial paralysis, dizziness
From a sight organ: often – uveitis; infrequently – occlusion of the retinal vein
From the vessels: Infrequent – vasculitis
With the respiratory system: very often – cough
From the digestive system: very often – diarrhea, vomiting, nausea, constipation
Skin and subcutaneous tissue disorders: very often – photosensitivity reaction, actinic keratosis, rash, maculo-papular rash, maculopapular rash, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn, hand-foot syndrome eritrodizestezii; often – erythema nodosum, keratosis pilaris, folliculitis; infrequently – toxic epidermal necrolysis, Stevens-Johnson syndrome
From the musculoskeletal system: very often – arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain, arthritis
Other: often – fatigue, fever, peripheral edema, asthenia
How to accept, acceptance rate and dosage
Treatment with Zelboraf should be carried out under the supervision of an oncologist.
Before using the drug Zelboraf should be held validated test for BRAF V600 mutations.
The recommended dose of the drug is Zelboraf 960 mg (4 tablets. 240 mg), 2 times / day (daily dose is 1920 mg) inwardly. Zelboraf can be taken at meal time, and apart from meals, but should avoid prolonged receiving both doses on an empty stomach.
The tablet should be swallowed whole with water. Chew or crush the tablet can not.
In a dry place, protected from light at a temperature not higher than 30 ° C
Substrates isozymes of cytochrome P450
The results of drug interaction in vivo, conducted in patients with metastatic melanoma, suggest that vemurafenib is a moderate inhibitor of CYP1A2 isoenzyme and an inducer of CYP3A4 isoenzyme. Vemurafenib can reduce exposure of substances metabolized mainly involving isoenzyme CYP3A4. In this regard, may reduce the effectiveness of contraceptive drugs metabolized with the participation of isoenzyme CYP3A4.
vemurafenib simultaneous use with drugs with a narrow therapeutic index, which is metabolized by the participation isozymes CYP1A2 and CYP3A4, it is not recommended because vemurafenib may modify their concentration. If it is impossible to avoid their joint use caution and to provide a reduced dose of the drug which is a substrate isoenzyme CYP1A2. Joint application with vemurafenib caffeine increases AUC (substrate isoenzyme CYP1A2) by an average of 2.6 times (up to 5 fold), whereas midazolam AUC (substrate isoenzyme CYP3A4) decreases on average by 39% (to a maximum of 80%). Dextromethorphan AUC (substrate CYP2D6) Dextrorphan and its metabolite increased by approximately 47% due to the effect on the kinetics of dextromethorphan which may be mediated by inhibition of isozyme CYP2D6. In a study in vitro vemurafenib a concentration of 10 uM caused weak inhibition of isozyme CYP2B6. It is not known whether vemurafenib when the equilibrium concentration of 100 .mu.M in the blood of patients (approximately 50 ug / ml) to reduce the content of substrates isoenzyme CYP2B6, such as bupropion, during their simultaneous use.
The simultaneous use of warfarin and vemurafenib (substrate isoenzyme CYP2C9) may lead to an increase in AUC last 18%. Care must be taken to provide additional monitoring MHO when used in combination vemurafenib svarfarinom.
In the in vitro study vemurafenib inhibited isoenzyme CYP2C8. The value of this observation to humans is unknown, but the risk of clinically significant effects on CYP2C8 isoenzyme substrates when used together can not be ruled out.
In order to avoid interaction with drugs after the cessation of the use of vemurafenib may require a washout period of 8 days.
In the course of in vitro studies have shown that vemurafenib is an inhibitor of P-glycoprotein, and BCRP (breast cancer resistance protein, breast cancer resistance protein). The clinical implications of these findings is unknown. We can not exclude possible increase exposure drugs transported by means of P-glycoprotein, while the use of vemurafenib (e.g., aliskiren, colchicine, digoxin, everolimus, fexofenadine), or BCRP (e.g., methotrexate, mitoxantrone, rosuvastatin). Data on the effect of vemurafenib on other transporters are missing.
The effect of drugs on vemurafenib
The in vitro studies demonstrated that vemurafenib metabolism occurs with the participation of isoenzyme CYP3A4 and by glyukuronirovaniya.Caution must be exercised while the use vemurafenib and potent inhibitors of isoenzyme CYP3A4, glyukuronirovaniya and / or transport proteins (e.g., ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).
Avoid the simultaneous application vemurafenib and potent inducers of P-glycoprotein, glyukuronirovaniya, isoenzyme CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, phenytoin or Hypericum perforatum) due to a possible reduction vemurafenib exposure.
The in vitro studies demonstrated that vemurafenib is a substrate of P-glycoprotein, and BCRP. Data on the effect of inducers or inhibitors of P-glycoprotein, and BCRP on exposure vemurafenib no. It is possible that the pharmacokinetic parameters vemurafenib may influence drugs that inhibit or influence the P-glycoprotein (e.g., verapamil, clarithromycin, cyclosporin, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) and BCRP (cyclosporine, gefitinib). < / p>
Before using the drug Zelboraf, patients should undergo a validated test for the BRAF V600 mutation. Efficacy and safety of Zelboraf drug in patients whose tumors carry the BRAF V600 mutations are rare, other than V600E and V600K, has not been conclusively proved. Zelboraf should not be used in patients with malignant melanoma expressing the BRAF wild-type.
When using the drug Zelboraf reported cases of serious hypersensitivity reactions, including anaphylaxis. Severe hypersensitivity reactions may include generalized rash, erythema or hypotension. With the development of severe hypersensitivity reactions, further reception Zelboraf drug should be discontinued.
When using the drug Zelboraf reported severe dermatological reactions, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the supporting clinical trial. With the development of severe dermatological reactions further receiving Zelboraf drug should be discontinued.
lengthening of the interval QT
Using the drug Zelboraf observed lengthening the interval QT, proportional vemurafenib exposure. Lengthening QT interval can increase the risk of ventricular arrhythmias, including ventricular tachycardia type “pirouette”. Use of the drug Zelboraf is not recommended in patients with impaired not amenable to correction fluid and electrolyte balance (including the balance magnesium) syndrome elongate interval QT, as well as in patients receiving drugs that contribute to lengthening of the interval QT.
and ECG study of water-electrolyte balance (including the balance magnesium) must perform before dosing and after dose change Zelboraf preparation. Subsequently registered ECG and electrolytes definition content recommended monthly for the first 3 months drug administration, and then every 3 months or more in the presence of clinical symptoms. If the interval QTc > 500 ms start receiving Zelboraf drug is not recommended. If during treatment QTc interval will be more than 500 ms, it is necessary to temporarily interrupt the reception Zelboraf preparation, to eliminate water and electrolyte abnormalities (including magnesium balance) correction and achieve elongation risk factors interval QT (e.g., chronic heart failure, bradyarrhythmias). After reducing the interval QTc to a value of less than 500 ms should be resumed taking the drug at a lower dose, as described in Tables 1 and 2. If after correction concomitant risk factors value interval QTc is > 500 ms and different from the initial values registered before taking the drug for more than 60 ms Zelboraf the drug should be stopped.
When applied Zelboraf drug were reported serious ophthalmic reaction include uveitis (including iritis) and retinal vein occlusion. Doctor should regularly monitor the patient for the development of ophthalmic reactions.
Squamous cell carcinoma of the skin
Patients treated with Zelboraf, cases of squamous cell carcinoma of the skin are described, including cases classified as keratoacanthoma and mixed keratoacanthoma. All patients are advised to undergo an examination by a dermatologist before taking the drug. If you have any suspicious skin lesions need to be excised, dermatopatologicheskoe directed to study and carry out treatment in accordance with local standards of care. With the development of squamous carcinoma of the skin of the patient is recommended to continue treatment with Zelboraf without dose adjustment. The doctor should carry out examination of the patient monthly during therapy and for 6 months after treatment and before the start of another anticancer therapy. Patients should be informed that in case of any skin changes, you must inform your doctor.
Squamous cell carcinoma other (nekozhnoy) localization
Patients treated with Zelboraf, registered cases of squamous cell carcinoma of other sites. Before the start of the drug is necessary to conduct a head and neck examination, consisting at least of a visual inspection of the mucous membranes of the mouth and palpation lymph nodes, and repeating this examination every 3 months during treatment. In addition, before taking the drug need to perform CT of the chest and during treatment to repeat this survey every 6 months.
Before you start taking the drug and at the end of therapy or the presence of clinical symptoms is recommended to study the rectum and pelvic organs (in women).
After discontinuation of the drug Zelboraf screening for squamous cell carcinoma of other sites should continue for 6 months or until the beginning of another anticancer therapy. Revealed pathological changes should be carried out in accordance with clinical practice.
A new focus of the primary melanoma
When using the drug Zelboraf were recorded cases of the emergence of new centers of primary melanoma. In all cases, treatment was surgery, and patients continued treatment without dose adjustment. Screening for skin lesions should be carried out in accordance with the guidelines given above for squamous cell carcinoma of the skin.
On the basis of the mechanism of action, vemurafenib may cause progression of malignancies associated with mutations in the RAS gene. Required to consider carefully the relationship between the expected benefits and potential risks of the drug in patients with a history or concomitant malignancies associated with mutations in the RAS.
Pathological changes in laboratory parameters characterizing the liver
On a reception Zelboraf drug may occur abnormal changes in laboratory parameters that characterize hepatic function. Before taking the drug to evaluate the activity of hepatic enzymes (transaminases and alkaline phosphatase), and the concentration of bilirubin, and during dosing should monitor these parameters monthly or more frequently in case of clinical symptoms. In identifying the pathological changes in laboratory parameters should reduce the dose, interrupt or stop taking the drug (Table 1).
Patients with impaired renal function
Correction starting dose in patients with renal insufficiency mild to moderate severity is not required. data are insufficient to determine the need for dose adjustment in patients with severe renal insufficiency.
Patients treated with the drug Zelboraf were reported photosensitivity reactions from mild to severe. All patients during treatment Zelboraf should avoid sun exposure. Patients taking the drug while staying outdoors should wear clothing that protects from the sun and use sunscreen with UVA (ultraviolet range A) – and UVB (ultraviolet radiation range B) – filters and lip balm (Sun Protection Factor ≥ 30) for protection against sunburn. When photosensitization reactions of 2 degrees (intolerance to) or above is recommended to change the dose (Table 1).
The effect of vemurafenib on other medicinal products
vemurafenib may increase the exposure of drugs that are metabolized mainly involving CYP1A2 isoenzyme, and reduce the exposure of drugs that are metabolized mainly involving isoenzyme CYP3A4, including oral contraceptives.
The need for correction of the dose of drugs metabolized mainly involving isozymes CYP1A2 and CYP3A4, should be assessed prior to drug therapy Zelboraf depending on the therapeutic index of the drug.
With the simultaneous use of the drug Zelboraf and warfarin should be careful and take into account the MNO.
The effect of drugs on vemurafenib
On vemurafenib pharmacokinetic parameters can be influenced by drugs that affect iigibiruyuschie or P-glycoprotein (e.g., verapamil, clarithromycin, cyclosporin, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine). If possible, avoid the simultaneous application of the drug Zelboraf with potent inducers of P-glycoprotein, glyukuronirovaniya, isoenzyme CYP3A4 (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, Hypericum perforatum). In order to preserve efficacy Zelboraf should consider alternative treatment options for inducing drugs with less potential.
Contraception for women and men
The women of childbearing age and men should use reliable methods of contraception throughout the course of the drug Zelboraf and for at least 6 months after stopping treatment. Zelboraf drug may reduce the effectiveness of hormonal contraceptives, in connection with which it is recommended to use an alternative or additional method of contraception.
The destruction of unused preparation or expired should be in accordance with local requirements.
The effect on the ability to drive vehicles and management mechanisms
Studies of the effect of the drug Zelboraf on ability to drive vehicles and working with machinery and mechanisms have not been conducted. Patients should be warned about the possible development of dizziness, disorders of the eyes and fatigue, which can be the basis for refusing to drive.
Pregnancy and lactation
is contraindicated during pregnancy and lactation.
Symptoms: The dose-limiting toxicity of the drug Zelboraf was shown in the form of a rash with itching and fatigue
Treatment: In case of suspected overdose should stop taking the drug Zelboraf and to appoint maintenance therapy. When side reactions necessary to assign appropriate symptomatic treatment. Specific antidote which can be used in cases of overdose drug Zelboraf, does not exist.