Indications
Imatinib Mesylate is used in newly diagnosed adults and children with Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) in the chronic phase. It is also used in patients with Ph+CML in blast crisis, in the accelerated phase, or in the chronic phase after interferon-alpha therapy has failed. Adults with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) can take it, and children with newly diagnosed Ph+ ALL receive it in combination with chemotherapy. Adults with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements are another group, as are adults with aggressive systemic mastocytosis who don't have the D816V c-Kit mutation or whose c-Kit mutational status is unknown. It is also given to adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRa fusion kinase (shown by mutational analysis or by fluorescence in situ hybridization [FISH] demonstrating CHIC2 allele deletion), and to patients with HES and/or CEL who are FIP1L1-PDGFRa fusion kinase negative or unknown. Imatinib Mesylate is further indicated for adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans, and for patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. Last, it is used as adjuvant treatment in adults after complete gross resection of Kit (CD117) positive GIST.
⚠️ Always consult a registered physician before taking any medicine.
Pharmacology
Imatinib is a small molecule protein-tyrosine kinase inhibitor. It strongly blocks the activity of the Bcr-Abl tyrosine kinase (TK), and also several receptor TKs: Kit (the receptor for stem cell factor, SCF, coded for by the c-Kit proto-oncogene), the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). It can also block the cellular events that follow activation of these receptor kinases.
Absorption and Distribution
Imatinib is well absorbed after oral administration, and Cmax is reached within 2 to 4 hours after the dose. Mean absolute bioavailability is 98%. Mean AUC goes up in proportion to the dose, across doses from 25 mg to 1,000 mg. Repeated dosing causes no significant change in the pharmacokinetics, and when Imatinib is given once daily, accumulation at steady state is 1.5 to 2.5 fold. At clinically relevant concentrations, in vitro experiments show plasma protein binding of approximately 95%, mostly to albumin and 1-acid glycoprotein.
Metabolism
CYP3A4 is the major enzyme that metabolises Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9 and CYP2C19, play a minor role. The main active metabolite circulating in humans is the N-demethylated piperazine derivative, which is formed mostly by CYP3A4. In vitro, its potency is similar to that of the parent Imatinib. Its plasma AUC is about 15% of the AUC for Imatinib. The N-demethylated metabolite, CGP74588, binds to plasma proteins in much the same way as the parent compound.
Excretion
Imatinib is eliminated mainly in the feces, mostly as metabolites. In a study using an oral 14C-labeled dose, based on how much of the compound was recovered, approximately 81% of the dose was eliminated within 7 days. Feces accounted for 68% of the dose and urine for 13%. Unchanged Imatinib made up 25% of the dose (5% in urine, 20% in feces), and the rest was metabolites. After oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.
Pregnancy & Breastfeeding
Women of childbearing potential: Women who could become pregnant must be advised to use effective contraception while taking Imatinib and for at least 15 days after stopping it.
Pregnancy: There are limited data on imatinib in pregnant women. Since the medicine came on the market, there have been reports of spontaneous abortions and congenital anomalies in infants born to women who had taken Imatinib. Animal studies have shown reproductive toxicity, but the potential risk to the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used, the patient must be told about the potential risk to the foetus.
Breast-feeding: Not much is known about how imatinib passes into human milk. Studies in two breast-feeding women showed that both imatinib and its active metabolite can pass into the milk. In one patient, the milk plasma ratio was 0.5 for imatinib and 0.9 for the metabolite, which suggests that more of the metabolite reaches the milk. If you add the two concentrations together and take the most milk an infant drinks in a day, the total exposure should be low (around 10% of a therapeutic dose). But the effects of low-dose exposure on an infant are unknown, so women should not breast-feed during treatment and for at least 15 days after stopping Imatinib.
Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were seen. No studies have been done in patients taking Imatinib to look at its effect on fertility and gametogenesis. Patients who are worried about their fertility while on Imatinib should talk to their doctor.
⚠️ Talk to your doctor before taking any medicine during pregnancy or while breastfeeding.
Dosage Reference
⚠️ Reference ranges from official sources only. Consult your doctor for personalized dosing.
Side Effects & Interactions
Side Effects
No side-effect data recorded yet.