Iminox Mechanism of Action

Pharmacotherapeutic group: protein-tyrosine kinase inhibitor. ATC code: L01XE01.
Pharmacology: Pharmacodynamics: Mechanism of action: Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the BCR-ABL tyrosine kinase (TK), as well as 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). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.
Pharmacodynamic effects: Imatinib is a protein-tyrosine kinase inhibitor, which potently inhibits the breakpoint cluster region-Abelson (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 leukemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukemia (ALL) patients. In colony transformation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows selective inhibition of BCR-ABL positive colonies from 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 (PDGFR) and stem cell factor (SCF), KIT, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumour (GIST) cells, which express an activating KIT mutation. Constitutive activation of the PDGFR or the ABL protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. In addition, constitutive activation of KIT or the PDGFR has been implicated in the pathogenesis of ASM. Imatinib inhibits signaling and proliferation of cells driven by dysregulated PDGFR, KIT and ABL kinase activity.
Constitutive activation of KIT or the PDGFR has been implicated inthe pathogenesis of ASM.
Pharmacokinetics: The pharmacokinetics of Iminox 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%. The coefficient of variation for plasma imatinib AUC is in the range of 40% to 60% after an oral dose. When given with a high fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in C_max and prolongation of t_max by 1.5 h), with a small reduction in AUC (74%) compared to fasting conditions. The effect of gastrointestinal surgery on drug absorption has not been investigated.
Distribution: At 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.
The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, acyclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC₅₀ 50 μM) and fluconazole (IC₅₀ 118 μM) showed inhibition of imatinib metabolism which could have clinical relevance.
Imatinib was shown in vitro to be a competitive inhibitor of a marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/l, respectively. Maximal plasma concentrations of imatinib in patients are 2-4 μmol/l, consequently an inhibition of CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did not interfere with the biotransformation of 5-fluororacil, but it inhibited paclitaxel metabolism as a result of competitive inhibition of CYP2C8 (K_i = 34.7 4 μM). This Ki value is far higher than the expected plasma levels of imatinib in patients, consequently no interaction is expected upon co-administration of either 5-fluororacil or paclitaxel and imatinib.
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 and urine. Unchanged imatinib accounted for 25% of the dose, the remainder being metabolites.
Plasma pharmacokinetics: The t_½ 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 to 1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5 to 2.5-fold at steady state when dosed once daily.
Pharmacokinetics in GIST patients: In patients with GIST steady-state exposure was 1.5-fold higher than that observed for CML patients for the same dosage (400 mg daily). Based on population pharmacokinetic analysis in GIST patients, there were three variables (albumin, WBC and bilirubin) found to have a significant relationship with imatinib pharmacokinetics. Decreased values of albumin caused a reduced clearance (CL/f); and higher levels of WBC led to a reduction of CL/f. However, these associations are not sufficiently pronounced to warrant dose adjustment. In this patient population, the presence of hepatic metastases could potentially lead to hepatic insufficiency and reduced metabolism.
Population pharmacokinetics: Based on population pharmacokinetics analysis in CML patients, there was a small effect of age on the volume of distribution. This change is not thought to be clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib.
Pharmacokinetics in children: As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients. 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.
Based on population pharmacokinetic analysis in paediatric patients with haematological disorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, bodyweight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m² once daily (not exceeding 400 mg once daily) or 340 mg/m² once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.
Organ function impairment: Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib.
Although pharmacokinetic analysis showed that there is considerable inter subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function.