Download Imatinib

Imatinib
Trade Names
STI571, Gleevec
Classification
Signal transduction inhibitor
Category
Chemotherapy drug
Drug Manufacturer
Novartis
Mechanism of Action
Phenylaminopyrimidine methanesulfonate compound that occupies
the ATP binding site of the BCR-ABL protein and other related tyrosine
kinases. Binding in this ATP pocket results in subsequent inhibition
of substrate phosphorylation.
Potent and selective inhibitor of the P210 BCR-ABL tyrosine kinase
resulting in inhibition of clonogenicity and tumorigenicity of BCRABL
and Ph+ cells.
Induces apoptosis in BCR-ABL positive cells without causing cell
differentiation.
Inhibits other activated ABL tyrosine kinases, including P185 BCRABL,
and inhibits other receptor tyrosine kinases for platelet-derived
growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit.
Mechanism of Resistance
Increased expression of BCR-ABL tyrosine kinase through amplification
of the BCR-ABL gene.
Alterations in the binding affinity of the BCR-ABL tyrosine kinase to
the drug as a result of mutations in the protein.
Increased expression of P170 glycoprotein resulting in enhanced
drug efflux and decreased intracellular drug accumulation.
Increased degradation and/or metabolism of the drug through as yet
undefined mechanisms.
Absorption
Oral bioavailability is nearly 100%.
Distribution
Extensive binding (95%) to plasma proteins, including albumin and
_1-acid glycoprotein. Steady-state drug concentrations are reached in 2–3 days.
Metabolism
Metabolism in the liver primarily by the CYP3A4 microsomal enzyme.
Other cytochrome P450 enzymes play a minor role in its metabolism.
The main metabolite is the N-desmethylated piperazine derivative, and
this metabolite shows in vitro potency similar to that of the parent drug.
Elimination is mainly in the feces, predominantly as metabolites. The terminal
half-life of the parent drug is 18 hours, while that of its main metabolite,
the N-desmethyl derivative, is on the order of 40 hours.
Indications
Chronic phase of CML—First-line therapy in adult patients,
FDA-approved.
Chronic phase of CML after failure on interferon-_ therapy—
FDA-approved.
CML in accelerated phase and/or in blast crisis—FDA-approved.
Chronic phase Ph+ CML in pediatric patients whose disease has
recurred after stem cell transplant or is resistant to interferon-_.
Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated
with PDGFR gene rearrangements.
Hypereosinophilic syndrome/chronic eosinophilic leukemia
(HES/CEL).
Relapsed/refractory Ph+ acute lymphocytic leukemia (PH+ ALL).
Gastrointestinal stromal tumors (GIST) expressing c-kit (CD117).
Dosage Range
Recommended starting dose is 400 mg/day for patients in chronic
phase CML and 600 mg/day for patients in accelerated phase or
blast crisis. Dose increases from 400 mg to 600 mg or 800 mg in
patients with chronic phase disease, or from 600 mg to a maximum
of 800 mg (given as 400 mg twice daily) in patients with accelerated
phase or blast crisis may be considered in the absence of severe
adverse drug reaction and severe nonleukemia-related neutropenia
or thrombocytopenia in the following circumstances: disease progression
(at any time); failure to achieve a satisfactory hematological
response after at least 3 months of treatment; failure to achieve a
cytogenetic response after 12 months of treatment; or loss of a previously
achieved hematological and/or cytogenetic response. Patients
should be monitored closely following dose escalation given the
potential for an increased incidence of adverse reactions at higher
dosages.
Recommended starting dose is 400 mg/day for patients with GIST.
Limited data exist on the effect of dose increases from 400 mg to
600 mg or 800 mg in patients progressing at the lower dose.
Recommended starting dose is 400 mg/day for patients with
MDS/MPD.
Recommended starting dose is 400 mg/day for patients with
HES/CEL.
Recommended starting dose is 600 mg/day for patients with
Ph+ ALL.
Drug Interaction 1
Dilantin and other drugs that stimulate the liver microsomal CYP3A4
enzyme, including carbamazepine, rifampin, phenobarbital, and St. John’s
wort—These drugs increase the rate of metabolism of imatinib resulting in
its inactivation.
Drug Interaction 2
Drugs that inhibit the liver microsomal CYP3A4 enzyme, including
ketoconazole, itraconazole, erythromycin, and clarithromycin—These drugs
decrease the rate of metabolism of imatinib resulting in increased drug
levels and potentially increased toxicity.
Drug Interaction 3
Warfarin—Patients on coumarin-derived anticoagulants should be closely
monitored for alterations in their clotting parameters (PT and INR) and/or
bleeding as imatinib inhibits the metabolism of warfarin by the liver P450
system. Dose of warfarin may require careful adjustment in the presence of
imatinib therapy.
Special Considerations
Patients should be weighed and monitored regularly for signs and
symptoms of fluid retention. The risk of fluid retention and edema
is increased with higher drug doses and in patients whose age
_65 years.
Use with caution in patients with underlying hepatic impairment.
At this time, there is no specific recommendation regarding initial
dose adjustment in the setting of liver dysfunction.
Monitor CBC on a weekly basis for the first month, biweekly for the
second month, and periodically thereafter.
Imatinib should be taken with food and a large glass of water To Whom It May Concern:
decrease the risk of GI irritation.
Hematologic responses typically occur within 2 weeks after initiation
of therapy while complete hematologic responses are observed
within 4 weeks after starting therapy.
Cytogenetic responses are observed as early as 2 months and up to
10 months after starting therapy. The median time to best cytogenetic
response is about 5 months.
Carefully monitor dose of drug when used in patients with seizure
disorders on phenytoin. Dose of drug may need to be increased as
the metabolism of imatinib by the CYP3A4 enzyme is enhanced in
the presence of phenytoin.
Patients who require anticoagulation should receive low-molecular
weight or standard heparin as imatinib inhibits the metabolism of
warfarin.
Monitor cardiac function before (baseline) and periodically during
therapy with either MUGA radionuclide scan or echocardiogram to
assess LVEF. The diagnosis of CHF should be considered in patients
who experience edema while on imatinib.
Pregnancy category D.
Toxicity 1
Nausea and vomiting occur in 40%–50% of patients. Usually related to
the swallowing of capsules and relieved when the drug is taken with food.
Toxicity 2
Transient ankle and periorbital edema. Usually mild to moderate in
nature.
Toxicity 3
Occasional myalgias.
Toxicity 4
Fluid retention with pleural effusion, ascites, pulmonary edema, and
weight gain. Usually dose-related and more common in elderly patients and
in those in blast crisis and the accelerated phase of CML. CHF is a rare but
serious adverse event.
Toxicity 5
Diarrhea is observed in 25%–30% of patients.
Toxicity 6
Myelosuppression with neutropenia and thrombocytopenia.
Toxicity 7
Mild, transient elevation in serum transaminases. Clinically asymptomatic
in most cases.
Toxicity 8
Skin toxicity in the form of bullous reactions, including erythema multiforme
and Stevens-Johnson syndrome.