PSRmini safety relays

Indian Journal of Pharmacology 2002; 34:
strates like simvastatin, cyclosporin and pimozide
may have their plasma levels increased by imatinib.
Imatinib is an example of a successful outcome of
molecular targeting of the cancer-causing proteins
in the treatment of cancer. The US Food and Drug
Administration reviewed the marketing application
for this drug in less than three months under its "accelerated approval" regulations that allow FDA to
approve drugs for serious or life-threatening illnesses. FDA also approved imatinib under FDA's
"orphan drug program", which provides financial incentives for drugs developed to treat rare diseases.
The rapid development and review made this product available soon for the leukemia patients who
desperately need it.
Therapeutic trials: The efficacy of imatinib has been
evaluated in the form of hematological and
cytogenetic responses in multicentric, noncomparative studies in adults with Ph+CML in chronic
(after failure of interferon-alfa (IFN) therapy), accelerated and blast phase. The complete hematological response (CHR) in chronic phase was defined
as white cell count [WBC <10 x109/L] and platelet
count <450 x109/L maintained for at least 4 weeks.
The cytogenetic response was defined, by the percentage of Ph+metaphases in bone marrow, as:
complete (no cells Ph+), partial (1- 35%), minor (3665%) and absent (>65% cells Ph+).
Mechanism of action: Most patients with chronic
myeloid leukemia (CML - a rare life-threatening form
of cancer) have a translocation of chromosomes 9
and 22, leading to formation of abnormal chromosome, the Philadelphia chromosome (Ph+). This
leads to the production of an abnormal protein tyrosine kinase called BCR-ABL. This enzyme contributes to the uncontrollable proliferation and reduced
apoptosis of malignant white blood cells.
In 532 patients with chronic phase CML, complete
hematological responses (CHR) were achieved in
88% of patients and major cytogenetic responses in
49% in patients, using imatinib 400 mg/d.
Imatinib, a tyrosine kinase inhibitor with specific activity against BCR-ABL tyrosine kinase, stops cell
proliferation and can induce apoptosis of tumour
cells. Imatinib functions as a competitive inhibitor of
ATP, blocks the binding of ATP and inhibits kinase
Pharmacokinetics: Imatinib is well-absorbed
(98%) following oral administration. Cmax is achieved
within 2-4 h post-dose. Protein binding is about
95%. Mostly metabolized by the CYP3A4 enzyme
system to N-desmethyl imatinib, which is as active
as imatinib. Excreted mostly in feces (68% of dose)
as metabolites. 5% excreted unchanged in urine.
Half-lives of Imatinib and N-desmethyl imatinib are
18 and 40 h respectively.
Blood levels and effects are increased by concurrent use of inhibitors of enzyme CYP3A4 such
as grapefruit juice, erythromycin, clarithromycin
ketoconazole and itraconazole. Drugs that induce
CYP3A4 such as phenytoin, dexamethasone,
carbamazepine, rifampicin and phenobarbital may
decrease its blood levels and effects. CYP3A4 sub-
Complete hematological responses (CHR) were
achieved in 63% of patients and major cytogenetic
responses in 21% in patients with accelerated phase
CML, using imatinib 400-600 mg/d in 235 patients.
In 260 patients with blast crisis CML, complete hematological responses (CHR) were achieved in 26%
of patients and major cytogenetic responses in
13.5%, using imatinib 400-600 mg/d.
Complete hematological responses (CHR) were
achieved in 19 of 32 patients with Ph+acute
lymphoblastic leukemia (ALL) in a pilot study.
In vitro studies demonstrate imatinib is not entirely
selective; it also inhibits the receptor tyrosine kinases
for platelet-derived growth factor (PDGF), c-Kit and
stem cell factor (SCF) and inhibits PDGF- and SCFmediated cellular events. Its activity against c-Kit
makes it useful in the treatment of patients with
metastatic gastrointestinal stromal tumours (GIST).
Clinical improvement was demonstrated in 89% of
36 patients with GIST unresponsive to the standard
chemotherapy during treatment with 400- 600 mg/d
oral imatinib in a phase II trial.
Tolerability: Most adverse events reported in clinical trials were mild to moderate in severity. 68% of
patients reported nausea and vomiting. Hemorrhage
occurred in 13% of the patients who failed interferon
therapy and in 48% of those with a myeloid blast
crisis. Serious adverse effects reported included
severe fluid retention that occurred in up to 68% but
could often be managed with diuretics. Neutropenia,
thrombocytopenia and hepatotoxicity have been
reported as life threatening adverse events. Regular
blood counts are therefore required. There has been
a report of acute liver failure, which could have been
related to an interaction with paracetamol. High
doses of paracetamol should therefore be avoided.
Contraindications and precautions: It is
contraindicated in hypersensitivity, pregnancy and
lactation. It should be used cautiously in hepatic
impairment (dosage reduction recommended if
bilirubin >3 times normal or liver transaminases >5
times normal), geriatric patients (increased risk of
edema) and children (safety not established). Not
much is known about its late toxicity and also about
its role in actually prolonging survival, which will be
clear only after 1-2 years of further follow up.
Compiled by: Dr. GEETA SHARMA
Williamson KL, Jarvis B. Imatinib-Adis New Drug
Profile. Drugs 2001;61:1765-74.
Department of Pharmacology,
Govt. Medical College,
Amritsar, Punjab
Edited by: Dr. R. BALARAMAN
e-mail:[email protected]
13-15 December, 2002
For further details, please contact:
Prof. R.S.R. Murthy
Convener, Scientific Services Committee
C/o. Pharmacy Department, Faculty of Tech. & Enggs.,
M.S. University of Baroda, Kalabhavan, Vadodara-390 001.
Phone: +91 265 434187, 418928,
Fax: +91 265 423898, 418927
E-mail: [email protected]