Pharmacotherapeutic Group: Protein-tyrosine kinase inhibitor. ATC Code: L01XE01.
Pharmacology: Pharmacodynamics: Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML patients.
In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl positive tumour cells.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.
Pharmacokinetics: Pharmacokinetics of imatinib: The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg.
Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state.
Absorption: Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated.
Distribution: At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein.
Metabolism: The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound.
Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites.
Elimination: Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose).
Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.
Plasma pharmacokinetics: Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily.
Pharmacokinetics in children: As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing.
Toxicology: Preclinical safety data: The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits.
Multiple dose toxicity studies revealed mild to moderate haematological changes in animals, accompanied by bone marrow changes in animals.
Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.
Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment.
In a 39-week monkey study, no NOAEL (no observed adverse effect level). Treatment resulted in worsening of normally suppressed malarial infections in these animals.
Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay.
In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses ≤20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg.
In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation.
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones.
In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach.
Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 30 mg/kg/day.
The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified.