Trexa Mechanism of Action

Pharmacology: Pharmacodynamics: Gefitinib belongs to drug class antineoplastic agents or protein kinase inhibitors. The epidermal growth factor (EGF) and its receptor (EGFR [HER1; ErbB1]) have been identified as key drivers in the process of cell growth and proliferation for normal and cancer cells. EGFR activating mutation within a cancer cell is an important factor in the promotion of tumour cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis. Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy. No clinically relevant activity has been shown in patients with known EGFR mutation-negative tumours. Most NSCLC tumours with sensitising EGFR kinase mutations eventually develop resistance to Gefitinib treatment, with a median time to disease progression of 1 year.
Pharmacokinetics: Absorption: Following oral administration of Gefitinib, absorption is moderately slow and peak plasma concentrations of Gefitinib typically occur at 3 to 7 hours after administration. Exposure to Gefitinib is not significantly altered by food.
Distribution: Gefitinib has a mean steady-state volume of distribution of 1400 l indicating extensive distribution into tissue. Plasma protein binding is approximately 90%. Gefitinib binds to serum albumin and alpha 1-acid glycoprotein.
Biotransformation: Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in excreta and 8 metabolites in plasma where the major metabolite identified was O-desmethyl Gefitinib.
Elimination: Gefitinib is excreted mainly as metabolites via the faeces, with renal elimination of Gefitinib and metabolites accounting for less than 4% of the administered dose. Gefitinib total plasma clearance is approximately 500 ml/min and the mean terminal half-life is 41 hours in cancer patients. Administration of Gefitinib once daily results in 2- to 8-fold accumulation, with steady-state exposures achieved after 7 to 10 doses. At steady-state, circulating plasma concentrations are typically maintained within a 2- to 3-fold range over the 24-hour dosing interval.
Hepatic impairment: 3-fold increase in exposure to Gefitinib in patients with moderate and severe hepatic impairment was observed.