Ibakin

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.

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.

Experience with Imatinib Mesylate at doses above the recommended therapeutic dose is limited. If an overdose happens, the patient should be observed and given suitable symptomatic treatment. In most of the reported cases the outcome was "improved" or "recovered". The events reported at different dose ranges are as follows.

Adult population

1200 to 1600 mg (duration varying between 1 to 10 days): nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache and decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): weakness, myalgia, increased creatine phosphokinase, increased bilirubin and gastrointestinal pain.

6400 mg (single dose): one case in the literature describes a patient who had nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count and increased transaminases.

8 to 10 g (single dose): vomiting and gastrointestinal pain have been reported.

Pediatric population

One 3-year-old male who took a single dose of 400 mg had vomiting, diarrhoea and anorexia. Another 3-year-old male who took a single dose of 980 mg had decreased white blood cell count and diarrhoea.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.

Keep Imatinib Mesylate in a cool, dry place, below 30°C. Protect it from light, and keep it out of the reach of children.