Erlotinib

Absorption

Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib.

Toxicity

Symptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia.

Description

Erlotinib is a tyrosine kinase inhibitor which acts on the epidermal growth factor receptor (EGFR), inhibiting EGFR-associated kinase activity (IC₅₀ = 2.5 μM). This inhibits tumor growth in human head and neck carcinoma HN5 tumor xenografts in mice with an ED₅₀ value of 9 mg/kg. Erlotinib also suppresses cyclin-dependent kinase 2 (Cdk2) activity in breast cancer cells (IC₅₀ = 4.6 μM) and JAK2 mutant JAK2^V617F positive hematopoietic progenitor cells (IC₅₀ = 5 μM), which is associated with polycythemia vera, idiopathic myelofibrosis, and essential thrombocythemia. Formulations containing erlotinib have been used to treat certain forms of cancer, including non-small cell lung cancer.

The Uses of Erlotinib

Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM.

The Uses of Erlotinib

antineoplastic;tyrosine kinase inhibitor

The Uses of Erlotinib

A tyrosine kinase inhibitor

Indications

Erlotinib is indicated for:
The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy.

What are the applications of Application

Erlotinib, Free Base is a tyrosine kinase inhibitor

Background

Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that is used in the treatment of non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is typically marketed under the trade name Tarceva. Erlotinib binds to the epidermal growth factor receptor (EGFR) tyrosine kinase in a reversible fashion at the adenosine triphosphate (ATP) binding site of the receptor. Recent studies demonstrate that erlotinib is also a potent inhibitor of JAK2V617F, which is a mutant form of tyrosine kinase JAK2 found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. This finding introduces the potential use of erlotinib in the treatment of JAK2V617F-positive PV and other myeloproliferative disorders.

Definition

ChEBI: A quinazoline compound having a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6- and 7-positions.

brand name

Tarceva (OSI).

General Description

Class: receptor tyrosine kinase
Treatment: NSCLC
Oral bioavailability = 60%
Elimination half-life = 36 h
Protein binding = 93%

Clinical Use

Erlotinib
Treatment of locally advanced or metastatic nonsmall cell lung cancer after failure of at least 1 other regime
Pancreatic cancer

Side Effects

• Burning, tingling, numbness or pain in the hands, arms, feet, or legs.
  
• cough or hoarseness.
• diarrhea (severe)
• difficult or labored breathing.
• fever or chills.
• rash (severe)
• sensation of pins and needles.
• stabbing chest pain.

Synthesis

The synthesis of Erlotinib is as follows:
N-dimethylformamidine, 0.72 g (6.15 mmol) of N '- [2-cyano-4,5-bis (2-methoxyethoxy) phenyl] ) Of 3-aminophenylacetylene and 8 mL of acetic acid were reacted in a 50 mL reaction flask at 125 ° C for 1 hour and cooled to room temperature.20 mL of ice water was added to the mixture, the pH was adjusted to 10 with aqueous ammonia, and the mixture was stirred for 1 hour, suction filtered and the filter cake washed with water until neutral.The filter cake was dried to obtain 2.15 g of erlotinib in a yield of 91.5%.

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: increased risk of bleeding with NSAIDs.
Antacids: concentration possibly reduced by antacids, give at least 4 hours before or 2 hours after erlotinib.
Anticoagulants: increased risk of bleeding with coumarins
Antipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosis.
Antivirals: avoid with boceprevir.
Ulcer-healing drugs: avoid with cimetidine, esomeprazole, famotidine, lansoprazole, nizatidine, pantoprazole and rabeprazole; concentration reduced by ranitidine, give at least 2 hours before or 10 hours after ranitidine; concentration reduced by omeprazole - avoid.

Metabolism

Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1.

Metabolism

Erlotinib is metabolised mainly by the cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and 1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib.
Metabolic pathways include demethylation, to metabolites OSI-420 and OSI-413, oxidation, and aromatic hydroxylation. The metabolites OSI-420 and OSI-413 have comparable potency to erlotinib in non-clinical in vitro assays and in vivo tumour models. They are present in plasma at levels that are <10 % of erlotinib and display similar pharmacokinetics as erlotinib. Erlotinib is excreted predominantly as metabolites via the faeces (>90%) with renal elimination accounting for only a small amount (approximately 9%) of an oral dose. Less than 2% of the orally administered dose is excreted as parent substance