Tarlonib Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Erlotinib potently inhibits the intracellular phosphorylation of HER1/EGFR. HER1/EGFR is expressed on the cell surface of normal cells and cancer cells. In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.
Pharmacokinetics: Absorption: Oral erlotinib is reported to be well absorbed and has an extended absorption phase, with mean peak plasma levels occurring at 4 hours after oral dosing. A reported study in normal healthy volunteers provided an estimate of bioavailability of 59%. The exposure after an oral dose may be increased by food. Following absorption, erlotinib is reported to be highly bound in blood, with approximately 95% bound to blood components, primarily to plasma proteins (i.e. albumin and alpha-1 acid glycoprotein [AAG]), with a free fraction of approximately 5%.
Distribution: Erlotinib has a mean apparent volume of distribution of 232 l and distributes into tumour tissue of humans. The primary active metabolites were present in the tumour at concentrations averaging 160 ng/g tissue, which corresponded to an overall average of 113% of the reported steady-state peak plasma concentrations. Tissue distribution studies using whole body autoradiography following oral administration with [¹⁴C]-labeled erlotinib in athymic nude mice with HN5 tumour xenografts have reported rapid and extensive tissue distribution with maximum concentrations of radio labeled drug (approximately 73% of that in plasma) observed at 1 hour.
Metabolism: Erlotinib is metabolized in humans by hepatic cytochrome P450 enzymes, primarily by CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib. In vitro studies have reported approximately 80-95% of erlotinib metabolism by the CYP3A4 enzyme. There are three main metabolic pathways identified: 1) O-demethylation of either side chain or both, followed by oxidation to the carboxylic acids; 2) oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and 3) aromatic hydroxylation of the phenyl-acetylene moiety. The primary metabolites of erlotinib produced by O-demethylation of either side chain have comparable potency to erlotinib in preclinical 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.
Elimination: The metabolites and trace amounts of erlotinib are reported to be excreted predominantly via the feces (>90%), with renal elimination accounting for only a small amount of an oral dose.
Clearance: A population pharmacokinetic analysis in patients receiving single-agent erlotinib has reported a mean apparent clearance of 4.47 l/hour with a median half-life of 36.2 hours. Therefore, the time to reach steady-state plasma concentration would be expected to occur in approximately 7-8 days. No significant relationships between predicted apparent clearance and patient age, body weight, gender, and ethnicity were observed.
Patient factors, which correlate with erlotinib pharmacokinetics, are serum total bilirubin, AAG concentrations and current smoking. Increased serum concentrations of total bilirubin and AAG concentrations were associated with a slower rate of erlotinib clearance. Smokers had a higher rate of erlotinib clearance (see Interactions).
A second population pharmacokinetic analysis was reported that incorporated erlotinib data from pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis reported that covariates affecting erlotinib clearance in patients from the pancreatic study were very similar to those reported in the prior single-agent pharmacokinetic analysis. No new covariate effects were reported. Co-administration of gemcitabine had reported no effect on erlotinib plasma clearance.
Pharmacokinetics in Special Populations: There have been no specific studies reported in pediatric or elderly patients.
Hepatic impairment: Erlotinib is mainly cleared by the liver. Erlotinib exposure was reported to be similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
Renal impairment: Erlotinib and its metabolites are not significantly excreted by the kidneys, as less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.
Smokers: A pharmacokinetic study in nonsmoking and currently cigarette-smoking healthy subjects has reported that cigarette smoking leads to increased clearance of, and decreased exposure to, erlotinib. The AUC_0-infinity in smokers was reported to be about 1/3 of that in never/former smokers. This reduced exposure in current smokers is presumably due to induction of CYP1A1 in lung and CYP1A2 in the liver.