Sorafenib
When ATH: L01XE05
Pharmacological action
Farmakodinamika
Sorafenib is a multi-kinase inhibitor. Reduces the proliferation of cells in vitro opuholvyh. Displaying, that sorafenib inhibits multiple intracellular kinase (c-CRAF, Nice nice и мутантную) and kinase, located at the cell surface (KIT, FLT- 3, RIGHT, VEGFR-1, VEGFR- 2, VEGFR-3 и PDGFR- ß). It is believed, that some of these kinases involved in tumor cell signaling systems, in angiogenesis and apoptosis. Sorafenib inhibits tumor growth in the hepatocellular carcinoma and renal cell carcinoma in humans.
Pharmacokinetics
After receiving sorafenib tablets, its average relative bioavailability of 38-49%. The half-life of sorafenib is approximately 25-48 hours. It is receiving repeated doses of sorafenib for 7 days resulted in a 2.5-7 fold increase in storage, compared with a single dose.
The equilibrium concentrations of sorafenib in plasma are reached within 7 days, the ratio of maximum / minimum concentration is less than 2.
Absorption and distribution
Maximum concentration (FROMmax) sorafenib in plasma are reached after about 3 hours after ingestion. When taken with food fat with moderate bioavailability sorafenib approximates the bioavailability in the fasting. When taken with a meal high in fat reduced bioavailability by approximately 29 % versus drug-fasting. In appointing oral doses, exceeding 400 mg 2 once a day, On averagemax and area under the curve "concentration - time" (AUC) increase is not proportional.
Contact proteins – 99.5 %.
Metabolism and excretion
Metabolism of sorafenib made, mainly, in the liver by oxidation, mediated by CYP3A4 isoenzyme, and by glyukuronirovaniya, mediated by UGT1A9. Conjugates sorafenib can be cleaved in the gastrointestinal tract due to bacterial glucuronidase activity, allowing reabsorbed unconjugated drug. The simultaneous use of neomycin affects this process, decreasing the mean bioavailability of sorafenib to 54 %.
Upon reaching equilibrium in the sorafenib accounted for approximately 70-85 %. Identified 8 metabolites of sorafenib, 5 They are found in plasma. The main circulating metabolite of sorafenib in plasma – pyridine N-oxide, It has in vitro activity, similar to the activity of sorafenib, and approximately 9-16%.
After oral doses 100 mg sorafenib in the form of solution for 14 days displayed 96% of the administered dose, 77% excreted in the feces, 19% – the urine in the form of glucuronides. Unchanged sorafenib, in an amount 51% of the administered dose, determined in the stool.
Pharmacokinetics in special populations
Analysis of demographic data indicates, that the correction of the dose depends on the age or sex not required.
Children
The data on the pharmacokinetics of the drug in children missing.
Renal failure
Sorafenib studied pharmacokinetics after a single dose 400 mg in patients with normal renal function and patients with mild (creatinine clearance (CC) 50-80 ml / min.), moderate (KK from 30 to < 50 ml / min.) and heavy (CC < 30 ml / min.) decrease in renal function, not requiring dialysis. Effect of reduction of renal function on the pharmacokinetics of sorafenib were found. For patients with mild, moderate or severe loss of kidney function, not requiring hemodialysis, need to reduce the dosage offline.
Hepatic failure
Sorafenib appears, mainly, liver. Patients with mild (Class A classification Child-Pugh) or moderately (Class B classification Child-Pugh) impaired liver function, The pharmacokinetic parameters were the same sorafenib, both in patients with normal hepatic function. In patients with severely impaired hepatic function (Class C classification Child-Pugh) The pharmacokinetics of sorafenib has not been studied.
Testimony
- Metastatic renal cell carcinoma.
- Hepatocellular carcinoma.
Contraindications
- Hypersensitivity to sorafenib or any other component of the drug.
- Pregnancy and lactation.
- Childhood (efficacy and safety have not been established).
Carefully:
- for skin diseases,
- with hypertension,
- when increased bleeding or a history of bleeding,
- unstable angina,
- myocardial infarction,
- in therapy in conjunction with docetaxel and irinotecan.
Dosing and Administration
The recommended daily dose of sorafenib 800 mg (4 for tablets 200 mg). The daily dose is administered in two doses (2 tablets 2 once a day), or between meals, or together with food, containing low or moderate amount of fat. The tablets swallowed, with a glass of water. Treatment is continued until, As long as the clinical efficacy of the drug, or until its unacceptable toxic effect. Development of possible adverse drug reactions may require temporary interruption and / or dose reduction of sorafenib. If necessary, the dose sorafenib can be reduced to 400 mg 1 once a day.
Recommendations to reduce the dose of sorafenib in the development of skin toxicity:
| The degree of skin toxicity | Episodes | Recommendations for dose modification of sorafenib |
| 1-I have a degree: numbness, dysesthesia, paraesthesia, painless swelling, erythema or discomfort in the arms or legs, which do not interfere with the normal activity of the patient | Anyone in a row | Treatment continued with local symptomatic treatment. |
| 2-I have a degree: erythema and swelling of the hands or feet, accompanied by pain, and / or discomfort, that restrict normal activity of the patient. | The first occurrence | Treatment continued with a reduced dose of Nexavar (400 mg per day 28 days) and using the local symptomatic therapy. If there is no improvement within 7 days – cm. below. If after a dose reduction level of toxicity returns to grade 0-1, through 28 sorafenib day dose was increased to full dose. |
| No reduction intensities skin symptoms in flow 7 days | Pause on Nexavar therapy 7 or more days (until dermal toxicity is not stopped, or its expression is reduced to 1 toxicity). With the resumption of therapy to reduce the dose of Nexavar 400 mg / day every day. | |
| 2-second or third Episode development skin Toxicity | Pause on Nexavar therapy 7 or more days (until dermal toxicity is not stopped, or its expression is reduced to 1 toxicity). With the resumption of therapy – to reduce the dose of Nexavar 400 mg / day daily. | |
| In the event skin toxicity 4-first time | Nexavar therapy should be discontinued. The decision to cancel care sorafenib should be based on clinical evaluation of the patient and his preferences. | |
| 3-I have a degree: moist desquamation, ulceration, blisters or severe pain in the hands or feet, or severe discomfort, svoiprofessionalnye not allow the patient to perform the duties and take care of themselves | The first appearance | Pause on Nexavar therapy 7 or more days (until dermal toxicity is not stopped, or its expression is reduced to 1 toxicity). Immediately appoint a local symptomatic therapy. At resuming therapy to reduce the dose of Nexavar 400 mg / day daily. If after a dose reduction level of toxicity back to 0-1 degrees, through 28 sorafenib day dose was increased to full dose |
| When second episode | Pause on Nexavar therapy 7 or more days (until dermal toxicity is not stopped, or its expression is reduced to 1 toxicity). Immediately appoint a local symptomatic therapy. With the resumption of therapy to reduce the dose of Nexavar 400 mg / day daily. | |
| When 3rd episode | Nexavar therapy should be discontinued. The decision to cancel sorafenib therapy should be based on clinical evaluation of the patient and his preferences. |
Certain groups of patients
Children
The safety and efficacy of sorafenib purpose has not been established in children.
Dose adjustment, depending on the age of the patient (senior 65 years), sex or body weight, not required.
Reduced liver function
In patients with decreased liver function class A and B classification Child-Pugh dosage adjustment is required. Treatment with sorafenib patients with decreased liver function of class C by Child-Pugh has not been studied.
Reduced renal function
Patients with mild, moderate and severe renal impairment (hemodialysis) It does not require dose reduction of sorafenib. The use of sorafenib in the treatment of patients, hemodialysis, not known. In patients at risk for impaired renal function should be monitored fluid and electrolyte balance.
Side effect
The following adverse events, marked by the application of Nexavar, distributed incidence according to the following gradation: Often (?1/10), often (from >= 1/100 to <1/10) infrequently (from >= 1/1000 to <1/100).
From the hematopoietic system: very often - lymphopenia; often - leukopenia, neutropenia, anemia, thrombocytopenia.
Cardio-vascular system: very often - bleeding (including bleeding from the gastrointestinal kishechnogotrakta, respiratory and cerebral hemorrhage), high blood pressure; often - congestive heart failure, "Tides" of blood to the face, rarely - hypertensive crisis, myocardial ischemia and / or myocardial infarction.
The respiratory system: often - hoarseness; infrequently - rhinorrhea, phenomena, similar to interstitial lung diseases (pneumonitis, Radiation pneumonitis, acute respiratory distress syndrome, interstitial pneumonia, pneumonitis, pneumonia).
Skin and skin appendages: very often - skin rash, alopecia, palmar-plantar eritrodizesteziya, эritema, itching; often - exfoliative dermatitis, acne, xerosis, peeling of the skin; infrequently - folliculitis, eczema, erythema multiforme, keratoacanthomas / ploskokletočnaâ skin cancer, Stevens-Johnson syndrome.
On the part of the digestive system: very often - diarrhea, nausea, vomiting, stomach ache; often - stomatitis, dryness of the oral mucosa, glossodiniya, dyspepsia, dysphagia, anorexia, constipation; rare - hastroэzofahealnыy reflux, gastritis, pancreatitis, perforation of the gastrointestinal tract, increased levels of bilirubin (including jaundice), cholecystitis, kholangit.
From the nervous system: often - peripheral sensory neuropathy; reversible encephalopathy syndrome.
Mental disorders: often - depression.
On the part of the hearing: often - ringing in the ears
On the part of the musculoskeletal system: Parts - arthralgia, myalgia.
From the urogenital system: often - renal failure.
Reproductive function: often - erectile dysfunction; rarely - gynecomastia.
On the part of the endocrine system: Infrequent - hypothyroidism, hyperthyroidism.
On the part of the immune system: rarely - hypersensitivity reactions (including skin reactions and urticaria).
Violations of laboratory parameters: very often - hypophosphatemia, increase in the level of lipase and amylase;
often - transient increase in transaminases (IS, GOLD);
infrequently - dehydration, giponatriemiya, transient increase in serum alkaline phosphatase, deviation from the normal level of the importance of international normalized ratio (INR) and prothrombin.
Other: very often - fatigue, pain of various localization (including pain in the oral cavity, abdominal pain, pain in the swelling, headache, pain in the extremities); Parts - asthenia, flu-like symptoms, fever, weight loss; infrequently – the accession of secondary infections.
In addition, In clinical studies, Nexavar has been reported rarely the following important from a medical point of view of adverse events: tranzitornaya ishemicheskaya attack, arrhythmia, thromboembolism. For these adverse events was not confirmed a causal relationship with the use of Nexavar.
A randomized controlled trial, aimed at comparing safety and efficacy of carboplatin and paclitaxel in combination with sorafenib or without the patients with NSCLC (NSCLC tumors) stages IIIB-IV, not previously treated with chemotherapy, It was stopped on the advice of the independent Data Monitoring Committee, that the study did not meet its primary ultimate goal – an increase in overall survival. Adverse events, noted in the study,, generally complied with the known safety profile of sorafenib, carboplatin and paclitaxel. But, in patients with squamous cell lung cancer, treated with carboplatin and paclitaxel in combination with sorafenib, had a higher mortality rate compared with patients, receiving only carboplatin and paclitaxel (hazard ratio 1.81, 95 %; confidence interval 1.19-2.74). Determine the cause of this phenomenon have been identified.
Overdose
In case of overdose may increase the above adverse events, especially diarrhea and skin reactions. Treatment of symptomatic. Antidote k sorafenibu not known.
Drug Interactions
CYP3A4 inductors: Preparations, inducing CYP3A4 activity (eg, rifampicin, phenytoin, Carbamazepine, phenobarbital, dexamethasone and preparatы, containing extract of the herb St. John's wort) may increase metabolism of sorafenib and, thus, reduce its concentration in the body.
CYP3A4 inhibitors: clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely cytochrome.
Substrate CYP2C9: Simultaneous treatment with sorafenib and warfarin did not lead to changes in the average values of prothrombin time and international normalized ratio (INR) compared to placebo. However, we recommend regular determination of the INR for all patients, receiving concomitant treatment with sorafenib and warfarin.
Substrates of specific isoenzymes of cytochrome P450 group: Sorafenib inhibits any, or induce isozymes of cytochrome P450 group.
Combination with other anticancer drugs: sorafenib not affect the pharmacokinetics of gemcitabine and oxaliplatin. Co-administration of sorafenib and doxorubicin leads to an increase in the maximum plasma concentration (IGC) of doxorubicin 21%. When concomitant administration of sorafenib and irinotecan, the active metabolite SN-38 is further metabolised involving UGT1A1, marked increase in BMD for SN-38 67-120% and an increase in BMD in the irinotecan 26-42 %. The clinical significance of these observations is not known. The simultaneous use of docetaxel (by 75 or 100 mg / m2 once through each 21 day) and sorafenib (200 or 400 mg 2 times a day with 2 by 19 day for a 21-day cycle) with a 3-day intervals before and after the appointment of docetaxel followed by an increase in AUC and Cmax docetaxel respectively 36-80 % and 16-32 %. When concomitant administration of sorafenib and docetaxel should be careful.
Neomycin
The simultaneous use of neomycin, non-systemic antibiotic, used for the eradication of gastrointestinal flora, It affects the enterohepatic circulation of sorafenib, leading to a decrease in sorafenib exposure. In healthy volunteers, treated for 5 dney neomycin, the mean bioavailability of sorafenib decreased to 54%. The clinical significance of these data is unknown. The influence of other antibiotics have not been studied, but will, most likely, depend on the ability to decrease glucuronidase activity.
Cautions
Treatment with sorafenib should be under the supervision of a specialist with experience in the use of anticancer drugs.
During therapy with sorafenib should periodically monitor the performance of peripheral blood (including differential blood count and platelets).
The most common adverse reactions while taking sorafenib were skin reactions in the extremities (palmar-plantar eritrodizesteziya) and rashes. In most cases they have been 1 and 2 severity and manifested, mainly, during the first six weeks of treatment with sorafenib. For treatment of dermal toxicity, local agents can be used with symptomatic effect. If you want to temporarily stop treatment and / or change the dose of sorafenib or, in severe or recurring cases of skin reactions, therapy sorafenib cancel.
Patients, treated with sorafenib, It was registered increase in the incidence of hypertension. Hypertension usually wore light or moderate, I observed at the beginning of treatment and treatable with standard antihypertensive drugs. During treatment with sorafenib should regularly monitor blood pressure and adjust its increase antihypertensive therapy. In cases of severe or persistent hypertension, or the appearance of hypertensive crisis, despite holding adequate antihypertensive therapy, should consider discontinuing treatment with sorafenib.
Sorafenib may increase the risk of bleeding. Heavy bleeding are rare. If you experience any bleeding, requiring medical intervention, It encouraged to consider discontinuing treatment with sorafenib.
The joint appointment of warfarin and sorafenib patients had some rare episodes of bleeding or increased international normalized ratio (INR). The joint appointment of sorafenib and warfarin need regular determination of prothrombin time, INR, Clinical signs of bleeding.
In the case of surgical interventions recommended the suspension of treatment with sorafenib position precaution. Clinical observations, concerning the reintroduction of sorafenib after surgery, very few. Therefore, the decision to resume sorafenib therapy after surgery should be based on the clinical evaluation of the adequacy of wound healing.
In the event of ischemia and / or myocardial infarction should be temporarily or permanently discontinue treatment with sorafenib. Perforation of the gastro-intestinal tract occurs infrequently and is described in less than 1% patients, sorafenib. In some cases, these events were associated with tumors in the peritoneal cavity. In the case of perforation of the gastro-intestinal
tract sorafenib treatment should be discontinued.
There are no data on the treatment of sorafenib in patients with severe hepatic impairment (Class C classification Child-Pugh). Since sorafenib is displayed, mainly, liver, in patients with severe hepatic impairment, may increase the effect of the drug.
Be wary appoint sorafenib with drugs, are metabolized / O mainly involving UGT1A1 (eg, Irinotecan).
The simultaneous use of docetaxel (75 or 100 mg / m2) and sorafenib (200 or 400 mg 2 once a day) 3-day intervals before and after the appointment of docetaxel accompanied by an increase in the AUC of docetaxel 36-80%. When concomitant administration of sorafenib and docetaxel should be careful.
The simultaneous use of neomycin may reduce the bioavailability of sorafenib.
Pregnancy, lactation, the effect on fertility.
Women should avoid becoming pregnant during treatment with sorafenib. Women with access to reproductive capacity should be informed of the potential hazard to the fetus sorafenib, which includes teratogenicity, challenges to the survival of the fetus and embryotoxicity. During and for at least 2 weeks after treatment with sorafenib must use reliable methods of contraception.
Unknown, whether sorafenib is allocated to human milk. Because many drugs are excreted in breast milk and the effect of sorafenib on infants have not been studied, women should abandon breastfeeding during treatment with sorafenib.
Studies of sorafenib in pregnant women were not conducted. Animal studies have shown reproductive toxicity of sorafenib, including the ability of a substance to cause malformations. In experiments in rats show, that sorafenib and its metabolites cross the placenta. Expected, that sorafenib inhibits angiogenesis in the fetus. Do animals have a selection of milk sorafenib and / or its metabolites.
