Pharmacodynamics Tarceva:
Tarceva Erlotinib – a potent inhibitor of the tyrosine kinase epidermal growth factor receptor HER1/EGFR (HER1 – epidermal growth factor receptor of human type I / EGFR – epidermal growth factor receptor). Tyrosine kinase responsible for phosphorylation of intracellular process HER1/EGFR. HER1/EGFR expressed on the surface of both normal and cancer cells. Inhibition of EGFR phosphotyrosine inhibits the growth of tumor cell lines and / or causes their death.
Pharmacokinetics Tarceva:
Absorption
Erlotinib is well absorbed after oral administration. The maximum plasma concentration is reached within 4 h after administration. Bioavailability in healthy volunteers is 59%. Simultaneous food intake can increase the bioavailability of erlotinib.
Distribution
The maximum plasma concentration – 1.995 ng / ml. The equilibrium concentration is reached at day 8. Before taking the next dose of erlotinib average minimum concentration in plasma is 1.238 ng / ml. The value of AUC in the range mezhdozovom when the equilibrium concentration of 41.3 ng / h / ml.
Samples of tumor tissue on day 9 of treatment the average concentration of erlotinib 1.185 ng / g tissue, which is 63% of the maximum plasma concentration at steady state. The concentration of the main active metabolite in tumor tissue – 160 ng / g, which corresponds to 113% of maximum plasma concentration at steady state. 1 hour after oral administration of erlotinib maximum drug concentration in plasma is approximately 73%. The degree of binding to plasma proteins (albumin and alpha-1 acid glycoprotein) – 95%.
Metabolism
Erlotinib is metabolized in the liver enzyme CYP3A4, with the participation, to a lesser extent – CYP1A2 and CYP1A1 isoforms lung. In vitro 80-95% of erlotinib is metabolized with the participation of CYP3A4. Metabolism occurs in three ways: In-dimetilirovanie of one side or both strands with further oxidation to carboxylic acids, the oxidation of acetylene moiety with subsequent hydrolysis to arilkarbonovoy acid, and aromatic hydroxylation of phenyl-acetylene moiety. The main metabolites are formed by B-dimetilirovaniya one of the side chains and have activity comparable to erlotinib. They are present in plasma at concentrations of
Breeding
The average clearance – 4.47 l / h. There were no communications with a creatinine clearance rate, age, weight, sex and race of the patient. The average half-life – 36.2 hours and trace amounts of metabolites of erlotinib are derived mainly from the faeces (> 90%) and in small quantities – in the urine.
Reduced clearance of erlotinib observed with increasing concentration of total bilirubin and alpha-1 acid glycoprotein, and its improvement – in smokers.
Pharmacokinetics in special populations
Specific studies in children and the elderly have been conducted.
Abnormal liver function
Erlotinib is mainly excreted in the bile, however there is currently no data on the impact of the presence of metastases in the liver and / or abnormal liver function on the pharmacokinetics of erlotinib.
Renal impairment
Erlotinib and its metabolites are excreted by the kidneys in small amounts – less than 9% of applied dose once. Clinical studies in patients with impaired renal function were not conducted.
INDICATIONS Tarceva:
locally advanced or metastatic nonsmall cell lung cancer after failure of one or more chemotherapy regimens.
First-line therapy for locally advanced, metastatic or unresectable pancreatic cancer pancreatic cancer in combination with gemcitabine.
APPLICATION Tarceva:
Metastatic nonsmall cell lung cancer: taking medication for 1 hour before or 2 hours after meals, 150 mg 1 time a day, continuously.
Pancreatic cancer: taking medication for 1 hour before or 2 hours after meals, 100 mg 1 time a day, continuously, in combination with gemcitabine.
CONTRAINDICATIONS Tarceva:
Hypersensitivity to erlotinib or to any other component of the drug.
SIDE EFFECTS Tarceva:
The most commonly reported adverse events regardless of causal relationship with drug intake are skin rash (75%) and diarrhea (54%), the majority – I-II degree and do not require additional therapeutic measures. Skin rashes and diarrhea III-IV severity was observed in 9 and 6% of patients with small cell lung cancer and 5% of patients with pancreatic cancer who received Tarceva, each of these side effects required treatment discontinuation in 1% of patients and dose adjustments – in 1-6% of patients. The median time to occurrence of rash – 8 days before the start of diarrhea – 12 days.
Side effects in patients who received monotherapy at a dose of 150 mg Tarceva dose of 100 mg in combination with gemcitabine, were as follows.
Gastrointestinal disorders: Frequent – anorexia, diarrhea, vomiting, stomatitis, dyspepsia, abdominal pain, gastrointestinal bleeding, some of which were associated with the simultaneous use of warfarin or NSAIDs.
Hepatobiliary System: Frequent – abnormal liver function (including increased ALT, AST, bilirubin in the blood), which are mostly held fast, mild to moderate severity, or associated with liver metastases.
On the part of the vision: common – conjunctivitis, dry keratoconjunctivitis, keratitis, isolated cases of corneal ulcer.
The respiratory system: often – cough, shortness of breath, nasal bleeding, in some cases – Interstitial lung disease (interstitial pneumonia, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome and lung infiltration, including cases with fatal outcome).
The nervous system and psychiatric: common – headache, neuropathy, and depression.
For the skin: common – a rash, alopecia, dry skin, itching.
Other: often – fever, fatigue, severe infection (with or without neutropenia, pneumonia, sepsis, inflammation of the fibrous subcutaneous tissue, decrease body weight).
SPECIAL INSTRUCTIONS Tarceva:
interstitial lung disease (rad) rad including fatal, are rarely observed in patients with NSCLC, pancreatic cancer or other solid tumors who received Tarceva. In patients with small cell lung cancer who received placebo or Tarceva frequency rad 0.8% in each group. The incidence of rad in patients with pancreatic cancer who received Tarceva and gemcitabine was 2.5% versus 0.4% in the group that received placebo and gemcitabine. The overall incidence of rad in patients treated with Tarceva, including use in combination with chemotherapy was 0.6%. Rad includes interstitial pneumonia, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome and lung infiltration. Most cases were associated with the rad at the same time or prior chemotherapy, radiotherapy, parenchymal lung disease in the history of metastatic lung or infection. With the development of new and / or progression of unexplained pulmonary symptoms (dyspnea, cough and fever) receiving Tarceva should be suspended pending clarification of the reasons. In the case of rad reception Tarceva should be discontinued and conduct the necessary treatment.
Diarrhea. If you have moderate to severe diarrhea, loperamide should be set. In some cases, a lower dose of erlotinib. In severe or persistent diarrhea, nausea, vomiting, anorexia or dehydration to the development of Tarceva and temporarily override the rehydration is carried out.
Special instructions regarding dosing
If necessary, dose adjustment is recommended to reduce the dose of the drug gradually to 50 mg.
Abnormal liver function. Be careful when appointing Tarceva in patients with impaired liver function.
Renal failure. Safety and efficacy in patients with impaired renal function have not studied.
Childhood. Safety and efficacy of Tarceva in patients under the age of 18 years were studied.
Pregnancy and breast-feeding. Safety of Tarceva in pregnancy in humans poorly understood. In the preclinical study of reproductive toxicity of erlotinib in doses close to therapeutic and / or at doses that have toxic effects in humans, establishes the presence of his embryotoxic properties. Therefore, women of reproductive age during treatment and for at least 2 weeks after it should use effective contraceptive methods. Treatment with erlotinib in pregnant women can only take place if the predominance of the effect of therapy for the mother of the potential risk to the fetus.
Breast-feeding. Is not known whether the drug in breast milk. Therefore, we must consider the potential risk of the drug on the newborn.
Effects on ability to driving and working with potentially dangerous machinery. Studies of the effect on ability to drive vehicles or use machines have been conducted, however the action of erlotinib is not associated with a potential violation of such activities.
INTERACTIONS Tarceva:
The use of the drug in combination with substrates or modulators of the enzyme CYP3A4 may need to correct their dose.
Inhibitors of CYP3A4 (ketoconazole) decrease erlotinib metabolism and increase its concentration in blood plasma. Inhibition of CYP3A4 metabolism under the effect of ketoconazole (oral dose of 200 mg 2 times a day for 5 days) increases the AUC of erlotinib by 86% and a maximum concentration of 69%. In the case of toxicity to reduce the dose of Tarceva.
CYP3A4 inducers (rifampicin) increase the metabolism of erlotinib and significantly reduce its concentration in blood plasma. Induction of metabolism involving CYP3A4, while taking rifampicin (600 mg orally 4 times a day for 7 days) leads to a decrease in the median AUC of erlotinib by 69%. The clinical significance of this observation is unclear. If possible, provide an alternative method of treatment without induction of CYP3A4.
Warfarin and other coumarin derivatives. Noted increase in the rate of the international normalized ratio (INR) and the risk of bleeding, including gastrointestinal bleeding. Patients who take warfarin or other coumarin derivatives, should regularly monitor the prothrombin time or INR.
OVERDOSE Tarceva:
a single dose of erlotinib oral dose of 1600 mg is carried out satisfactorily. When you receive erlotinib at a dose greater than recommended, you may experience serious side effects include diarrhea, skin rash and elevated liver enzymes in serum. In case of overdose treatment is stopped and symptomatic therapy.
