Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
Pharmacotherapeutic group: Anthracyclines and related substances
ATC Code: L01DB06
Idarubicin is a DNA intercalating anthracycline which interacts with the enzyme topoisomerase II and has an inhibitory effect on nucleic acid synthesis.
The modification of 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 has been shown to have a higher potency with respect to daunorubicin and to be an effective agent against murine leukaemia and lymphomas both by i.v. and oral routes. Studies in-vitro on human and murine anthracycline-resistant cells have shown a lower degree of cross-resistance for idarubicin compared with doxorubicin and daunorubicin. Cardiotoxicity studies in animals have indicated that idarubicin has a better therapeutic index than daunorubicin and doxorubicin. The main metabolite, idarubicinol, has shown, in-vitro and in-vivo, antitumoural activity in experimental models. In the rat, idarubicinol administered at the same doses as the parent drug, is clearly less cardiotoxic than idarubicin.
In vitro studies have shown plasma protein binding of at least 95% for this product. This fact should be borne in mind when considering its use in combination with other drugs.
In adults, following oral administration of 10 to 60 mg/m² idarubicin, idarubicin was rapidly absorbed with the maximum plasma concentrations of 4-12.65 ng/mL achieved in 1 to 4 hours after dosing. The terminal half-life was 12.7±6.0 hrs (mean±SD). Following intravenous administration of idarubicin in adults, the terminal half-life was 13.9±5.9 hrs, similar to that observed after the oral administration.
After i.v. administration, idarubicin is extensively metabolised to an active metabolite, idarubicinol, which is slowly eliminated with a plasma T½ ranging between 41-69 hours). The drug is eliminated by biliary and renal excretion, mostly in the form or idarubicinol.
Studies of cellular (nucleated blood and bone marrow cells) in leukaemic patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection.
Idarubicin and idarubicinol concentrations in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Idarubicin disappearance rates in plasma and cells were comparable, with a terminal half-life of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours.
Pharmacokinetic measurements in 7 paediatric patients receiving intravenous idarubicin hydrochloride in doses ranging from 15 to 40 mg/m² over the 3 days of treatment, showed a median idarubicin half-life of 8.5 hrs (range: 3.6-26.4 hrs). The active metabolite, idarubicinol, accumulated during the 3 days of treatment, exhibiting a median half-life of 43.7 hrs (range: 27.8-131 hrs). In a separate study, pharmacokinetic measurements in 15 paediatric patients receiving oral idarubicin hydrochloride in doses ranging from 30 to 50 mg/m2during the 3 days of treatment, the maximum plasma concentration of idarubicin was 10.6 ng/mL (range 2.7-16.7 ng/mL at the 40 mg/m² dose). The median terminal half-life of idarubicin of was 9.2 hrs (range: 6.4-25.5 hrs). Significant accumulation of idarubicinol was seen over the 3 day treatment period. The observed terminal half-life value of idarubicin after i.v. was comparable to that following oral administration in paediatric patients.
Since Cmax of idarubicin is similar in children and adults following oral administrations, absorption kinetics seem not to differ between adults and children.
Following both oral and i.v. administrations, the elimination half-life values of idarubicin in children and adults differ.
Total body clearance values of 30-107.9 L/h/m² for idarubicin reported for adults are higher than the values of 18-33 L/h/m² reported for paediatric populations Although idarubicin has a very large volume of distribution in both adults and children, suggesting that much of the drug is bound to tissues, the shorter elimination half-life and lower total body clearance are not entirely explained by a smaller apparent volume of distribution in children compared to adults.
Idarubicin has mutagenic properties and it is carcinogenic in rats.
Reproduction studies in animals have shown that idarubicin is embryotoxic and teratogenic in rats but not rabbits.
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