Zavedos Mechanism of Action

Pharmacology: Pharmacodynamics: Idarubicin hydrochloride is a DNA intercalating analogue of daunorubicin, which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity, which results in an increased rate of cellular uptake compared with doxorubicin and daunorubicin.
Idarubicin hydrochloride has been shown to have a higher potency with respect to daunorubicin and to be an effective agent against murine leukemia and lymphomas by IV routes. Studies in vitro on human and murine anthracycline-resistant cells have shown a lower degree of cross-resistance for idarubicin hydrochloride compared with doxorubicin and daunorubicin. Cardiotoxicity studies in animals have indicated that idarubicin hydrochloride has a better therapeutic index than daunorubicin and doxorubicin. The main metabolite, idarubicinol, has shown, in vitro and in vivo, antitumoral activity in experimental models. In the rat, idarubicinol, administered at the same doses as the parent drug, is clearly less cardiotoxic than idarubicin hydrochloride.
Pharmacokinetics: Intravenous: After IV administration to patients with normal renal and hepatic function, idarubicin hydrochloride is eliminated from systemic circulation with a terminal plasma half-life ranging between 11 and 25 hours and is extensively metabolized to an active metabolite, idarubicinol, which is more slowly eliminated with a plasma half-life ranging between 41 and 69 hours. The drug is eliminated by biliary and renal excretion, mostly in the form of idarubicinol.
Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemic patients have shown that peak cellular idarubicin hydrochloride concentrations are reached a few minutes after injection. Idarubicin hydrochloride and idarubicinol concentrations in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Idarubicin hydrochloride disappearance rates in plasma and cells were almost comparable with a terminal half-life of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours.
Special Populations: Hepatic and renal impairment. The pharmacokinetics of idarubicin hydrochloride in patients with hepatic and/or renal impairment have not been fully evaluated. It is expected that in patients with moderate or severe hepatic dysfunction, the metabolism of idarubicin hydrochloride may be impaired and lead to higher systemic drug levels. The disposition of idarubicin hydrochloride may also be affected by renal impairment. Therefore, a dose reduction should be considered in patients with hepatic and/or renal impairment (see Dosage & Administration and Precautions) and idarubicin hydrochloride is contraindicated in patients with severe hepatic and/or renal failure (see Contraindications).
Pediatric: Pharmacokinetic measurements in 7 pediatric patients receiving intravenous idarubicin hydrochloride in doses ranging from 15 to 40 mg/m²/3 day course of treatment, showed a median idarubicin half-life of 8.5 hours (range: 3.6 - 26.4 hours). The active metabolite, idarubicinol, accumulated during the 3 day therapy, exhibiting a median half-life of 43.7 hours (range: 27.8-131 hours).
Toxicology: Preclinical safety data: Idarubicin hydrochloride was genotoxic in most of the in vitro or in vivo tests performed. Intravenous idarubicin hydrochloride was carcinogenic, toxic to the reproductive organs, and embryotoxic and teratogenic in rats. No noteworthy effects on the mothers or offspring were seen in rats given intravenous idarubicin hydrochloride during the peri- and post-natal periods up to the dose of 0.2 mg/kg/day. It is not known whether the compound is excreted in breast milk. Intravenous idarubicin hydrochloride, like other anthracyclines and cytotoxic drugs, was carcinogenic in rats. A local safety study in dogs showed that extravasation of the drug causes tissue necrosis.
The LD₅₀ (mean values) of intravenous idarubicin hydrochloride was 4.4 mg/kg for mice, 2.9 mg/kg for rats and about 1.0 mg/kg for dogs. The main targets after a single dose were the hemolymphopoietic system and, especially in dogs, the gastrointestinal tract.
The toxic effects after repeated administration of intravenous idarubicin hydrochloride were investigated in rats and dogs. The main targets of intravenous idarubicin hydrochloride in the above animal species were the hemolymphopoietic system, gastrointestinal tract, kidney, liver, and male and female reproductive organs.
Concerning the heart, subacute and cardiotoxicity studies indicated that intravenous idarubicin hydrochloride was slightly to moderately cardiotoxic only at lethal doses while doxorubicin and daunorubicin produced clear myocardial damage at non-lethal doses.