Mechanism of Action and Pharmacodynamics

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

Pharmacokinetics

Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Its half-life is about 36 hours and it is cleared predominantly by CYP3A4 metabolism and to a lesser extent by CYP1A2.

Absorption and Distribution

Bioavailability of erlotinib following a 150 mg oral dose of TARCEVA is about 60% and peak plasma levels occur 4 hrs after dosing. Food increases bioavailability substantially, to almost 100%.

Following absorption, erlotinib is approximately 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters.

Metabolism and Elimination

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. Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).

A population pharmacokinetic analysis in 591 patients receiving single-agent TARCEVA showed a median half-life of 36.2 hours. Time to reach steady state plasma concentration would therefore be 7 – 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance (see Interactions section).

A second population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis demonstrated that covariates affecting erlotinib clearance in patients from the pancreatic study were very similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance.

Special Populations

Patients with Hepatic Impairment

Erlotinib is cleared predominantly by the liver. No data are currently available regarding the influence of hepatic dysfunction and/or hepatic metastases on the pharmacokinetics of erlotinib (see PRECAUTIONS - Patients with Hepatic Impairment, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION - Dose Modifications sections).

Patients with Renal Impairment

Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

Interactions

Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 2/3 (see PRECAUTIONS - DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION - Dose Modifications sections).

Pretreatment with the CYP3A4 inducer rifampicin for 7 days prior to Tarceva administration increased erlotinib clearance by 3-fold and reduced AUC by 2/3. In a separate study, treatment with rifampicin for 11 days, with coadministration of a single 450 mg dose of TARCEVA on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg TARCEVA dose in the absence of rifampicin treatment (see PRECAUTIONS – DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION – Dose Modifications sections).

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