Download Erlotinib

Erlotinib
N
HCl
NO
O
HN
O
O
Trade Names
Tarceva, OSI-774
Classification
Signal transduction inhibitor
Category
Chemotherapy drug
Drug Manufacturer
OSI, Genentech
Mechanism of Action
Potent and selective small molecule inhibitor of the EGFR tyrosine
kinase, resulting in inhibition of EGFR autophosphorylation and
inhibition of EGFR signaling.
Inhibition of the EGFR tyrosine kinase results in inhibition of
critical mitogenic and anti-apoptotic signals involved in proliferation,
growth, metastasis, angiogenesis, and response to chemotherapy
and/or radiation therapy.
Mechanism of Resistance
Mutation in the EGFR tyrosine kinase leading to decreased binding
affinity to erlotinib.
Presence of KRAS mutations.
Activation/induction of alternative cellular signaling pathways, such
as IGF-1R.
Absorption
Oral bioavailability is approximately 60% and is increased by food to
almost 100%.
Distribution
Extensive binding (90%) to plasma proteins, including albumin and
_1-acid glycoprotein, and extensive tissue distribution. Peak plasma levels
are achieved 4 hours after ingestion. Steady-state drug concentrations are
reached in 7–8 days.
Metabolism
Metabolism in the liver primarily by the CYP3A4 microsomal enzyme
and by CYP1A2 to a lesser extent. Elimination is mainly hepatic with excretion
in the feces, and renal elimination of parent drug and its metabolites
account for about 8% of an administered dose. The terminal half-life of the
parent drug is 36 hours.
Indications
FDA-approved as monotherapy for the treatment of locally advanced
or metastatic non–small cell lung cancer after failure of at least one
prior chemotherapy regimen.
FDA-approved in combination with gemcitabine for the first-line
treatment of patients with locally advanced unresectable or metastatic
pancreatic cancer.
Dosage Range
Non–small cell lung cancer—Recommended dose is 150 mg/day PO.
Pancreatic cancer—Recommended dose is 100 mg/day PO in combination
with gemcitabine.
Drug Interaction 1
Dilantin and other drugs that stimulate the liver microsomal CYP3A4
enzyme, including carbamazepine, rifampicin, phenobarbital, and St. John’s
wort—These drugs may increase the metabolism of erlotinib, resulting in
its inactivation.
Drug Interaction 2
Drugs that inhibit the liver microsomal CYP3A4 enzyme, including ketoconazole,
itraconazole, erythromycin, and clarithromycin—These drugs may
decrease the metabolism of erlotinib, resulting in increased drug levels and
potentially increased toxicity.
Drug Interaction 3
Warfarin—Patients receiving coumarin-derived anticoagulants should be
closely monitored for alterations in their clotting parameters (PT and INR)
and/or bleeding, as erlotinib may inhibit the metabolism of warfarin by the
liver P450 system. Dose of warfarin may require careful adjustment in the
presence of erlotinib therapy.
Special Considerations
Use with caution in patients with hepatic impairment, and dose
reduction and/or interruption should be considered.
Non-smokers and patients with EGFR-positive tumors are more sensitive
to erlotinib therapy.
Erlotinib should not be used in combination with platinum-based
chemotherapy as there is no evidence of clinical benefit.
Closely monitor patients for new or progressive pulmonary symptoms,
including cough, dyspnea, and fever. Erlotinib therapy should
be interrupted pending further diagnostic evaluation.
Dose of erlotinib may need to be increased when used in patients
with seizure disorders who are receiving phenytoin, as the metabolism
of erlotinib by the liver P450 system is enhanced in the presence
of phenytoin.
Coagulation parameters PT/INR should be closely monitored when
patients are receiving both erlotinib and Coumadin, as erlotinib may
inhibit the metabolism of Coumadin by the liver P450 system.
In patients who develop a skin rash, topical antibiotics such as
Cleocin gel or either oral Cleocin and/or oral minocycline may help.
Avoid grapefruit and grapefruit juice while on erlotinib therapy.
Pregnancy category D.
Toxicity 1
Pruritus, dry skin with mainly a pustular, acneiform skin rash.
Toxicity 2
Diarrhea is most common GI toxicity. Mild nausea/vomiting and
mucositis.
Toxicity 3
Pulmonary toxicity in the form of ILD manifested by increased cough,
dyspnea, fever, and pulmonary infiltrates. Observed in less than 1% of
patients and more frequent in patients with underlying pulmonary disease.
Toxicity 4
Mild to moderate elevations in serum transaminases. Usually transient
and clinically asymptomatic.
1.
Toxicity 5
Anorexia.
Toxicity 6
Conjunctivitis and keratitis.
Toxicity 7
Rare episodes of GI hemorrhage.