Erlotiniʙ
When ATH:
L01XX34
Pharmacological action
Potent inhibitor of tyrosine kinase epidermal growth factor receptor, responsible for the process of intracellular phosphorylation of EGF growth, the expression of which is observed on the surface of both normal, and tumor cells. Inhibition of EGF receptor phosphotyrosine inhibits the growth of tumor cell lines and / or leads to their death.
Pharmacokinetics
Well absorbed after oral administration. TCMax – 4 no. Bioavailability – 59%, meal increases the bioavailability. Cmax plasma – 1.995 ng / ml. TCSS – 7-8 days. Before taking the next dose Cmin – 1.238 ng / ml. Mezhdozovogo AUC in the range when the Css – 41.3 mcg x h / ml. The volume of distribution – 232 l (distribution in the tumor tissue). In tumor tissue samples (lung cancer, cancer of the larynx) on 9 day treatment concentration of erlotinib – 1.185 ng / g, what is 63% Cmax of plasma when the Css . The concentration of the main active metabolite in tumor tissue 160 ng / g, corresponding 113% Cmax plasma when the Css. Cmax in tumor tissues – about 73% the concentration of drug in plasma, TSmax in tissue – 1 no. Contact proteins (albumin and alpha-1 acid glycoprotein) – 95%. It is metabolized in the liver by the enzyme CYP3A4 (in vitro 80-95%), to a lesser extent CYP1A2 and the pulmonary isoform CYP1A1. Metabolism occurs in three ways: O-dimethylation one or both of the side chains followed by oxidation to carboxylic acid; oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acids; aromatic hydroxylation fenilatsetilenovoy moiety. The main metabolites (less 10% concentrations of erlotinib) are formed by O-dimethylation one of the side chains and have activity, comparable with erlotinib; gee pharmacokinetics similar pharmacokinetics эrlotiniba. Clearance – 4.47 l /. T1 / 2 - 36.2 no. Metabolites and trace amounts derived erlotinib, predominantly, with stool (more 90%), negligible quantity (less 9% single dose) – kidney. When the concentration of total bilirubin, and alpha-1 acid glycoprotein marked decrease in clearance of erlotinib, increase – smokers.
Testimony
Local-rasprostranёnnыy or metastaticheskiy nemelkokletochnыy cancer lёgkogo then neэffektivnosti primeneniya odnoy disease or chemotherapy scheme. The first-line treatment of locally, unresectable or metastatic pancreatic cancer (in combination with gemcitabine).
Contraindications
Hypersensitivity, pregnancy, lactation. Hepatic failure, Age to 18 years.
Dosage regimen
Inside, for 1 hours before or after 2 hours after a meal, 1 once a day. Non-small cell lung cancer: by 150 mg daily, protractedly. Pancreatic cancer: by 100 mg daily, long, in combination with gemcitabine. If signs of disease progression therapy is stopped. If necessary, reduce the dose gradually 50 mg.
Side effects
Frequently (regardless of causal relationship to drug): rash (69-75%) and diarrhea (48-54%), primarily 1 and 2 Article. gravity and require no. Rash and diarrhea 3/4 Article. severity (9% and 6% respectively, in patients with lung cancer and nemelkoletochnym 5% – in patients with pancreatic cancer). The average period of time before the rash 8-10 days, before diarrhea – 12-15 days. The incidence of side effects in monotherapy and in combination with gemcitabine: Often (more 10%); often (more 1% less 10%); infrequently (more 0.001% less 1%); rarely (more 0.0001 less 0.001%); rarely (me 0.0001%), including individual cases.
From the digestive system: Often – anorexia, diarrhea, vomiting, stomatitis, dyspepsia, abdominal pain, often – gastrointestinal bleeding, some of which are associated with the simultaneous intake of NSAIDs or warfarin, abnormal liver function (incl. AЛT, ACT, bilirubin), primarily, transitory, mild or moderate Art. severity or associated with liver metastases.
From the senses: Often – conjunctivitis, keratoconjunctivitis sicca; often – keratit (1 in the case of transition corneal ulcer).
The respiratory system: Often – cough, breathlessness, often – nose bleed; infrequently – interstitial lung disease (interstitial pneumonia, obliterating bronchiolitis, fibrosis lyegkikh, acute respiratory distress syndrome, infiltration lyogkïx, incl. fatal).
From the nervous system: Often – headache, Neuropathy, depression.
For the skin: Often – rash, alopecia, xerosis, itch.
Other: Often – fever, fatigue, chills, severe infections (pneumonia, sepsis) incl. neutropenic, fibrous cellulitis, weight loss.
Overdose
Symptoms: diarrhea, skin rash, increased activity of "liver" transaminases.
Treatment: simptomaticheskaya therapy.
Cautions
Interstitial lung disease (OUT), incl. fatal rarely diagnosed in patients with small cell lung cancer, pancreatic cancer or other. solid tumors, receiving the drug. The overall incidence of ILD in patients, including use in combination with chemotherapy – 0.6%. Most cases of ILD was associated with receiving concomitant chemotherapy or previously conducted, radiation therapy, parenchymal lung disease in history, or metastatic lung infection. With the development of new and / or progression of symptoms (breathlessness, cough and fever) the drug should be interrupted to determine the cause. In the case of ILD is necessary to cancel the preparation and conduct appropriate treatment. If you have severe or moderate diarrhea can assign loperamide. In some cases, you may need to reduce the dose of erlotinib. If severe diarrhea, or Sustainable, toshnote, anorexia, or vomiting with dehydration medication temporarily cancel and spend rehydration. During the treatment, and, least, within 2 weeks after it should use reliable methods of contraception.
Drug Interactions
You may need dose adjustment inducers or inhibitors of the enzyme CYP3A4. CYP3A4 inhibitors (incl. ketoconazole) reduce erlotinib metabolism and increase its concentration in plasma: applying a dose of ketoconazole 200 mg orally 2 twice a day for 5 days increases the AUC of erlotinib on 86% Cmax and to 69%. Care should be taken when using erlotinib in combination with inhibitors of CYP3A4. In the case of toxicity, you need to decrease the dose. CYP3A4 inductors (incl. rifampicin) increase erlotinib metabolism and significantly reduce its concentration in plasma: at a dose of rifampicin 600 mg orally 4 twice a day for 7 days to reduce erlotinib AUC 69% (the clinical significance is not installed). An increased international normalized ratio (INR) and the development of bleeding, including gastrointestinal, некоторые из которых были связаны с одновременным приемом варфарина. При одновременном применении варфарина и др. производных кумарина необходимо регулярно контролировать протромбиновое время или MHO.
