Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: anthracyclines and related substances, ATC Code L01DB06.
(L: antineoplastic agents and immunomodulating agents)
Cytotoxic antibiotic of the anthracycline family.
Idarubicin is a DNA intercalating anthracycline which interacts with the enzyme topoisomerase II and has an inhibitory effect on nucleic acid synthesis.
As a result of modification of position 4 on the anthracycline ring, idarubicin is highly lipophilic. Its cellular uptake is therefore higher than that of doxorubicin or daunorubicin.
The main metabolite, idarubicinol, has shown anti-tumoural activity in experimental models under in vitro and in vivo conditions.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties


After IV administration in patients with normal renal or hepatic function, idarubicin has a terminal half- life T1/2 of between 11 and 25 hours.
97% and 94% of idarubicin and the active metabolite idarubicinol, respectively, are protein bound with a concentration of 10 ng/mL.
The medicine has been assayed in the nucleated blood and bone marrow cells of patients with leukaemia. These studies show that the cellular concentrations of idarubicin reach their maximum a few minutes after injection. Idarubicin and idarubicinol concentrations in nucleated blood and bone marrow cells are more than 100 times greater than the plasma concentrations.
The extremely high total plasma clearance value (0.7 to 0.9 L/min), which is far superior to the expected hepatic rate, indicates slow clearance as a result of the high distribution of the product in the tissues and suggests the presence of extensive extra-hepatic metabolism.
Idarubicin is mostly transformed into an active metabolite, idarubicinol, which has a slower half-life of between 41 and 69 hours.
ZAVEDOS is eliminated from the cells and plasma at a comparably similar speed, and has a terminal half-life of about 15 hours.
Idarubicin undergoes extensive transformation to idarubicinol and is eliminated in the bile and urine.
At-risk populations:
Renal and hepatic impairment
The pharmacokinetics of idarubicin in patients with renal and/or hepatic impairment has not been fully studied. It is likely that, in patients with moderate to severe hepatic dysfunction, the metabolism of idarubicin could be altered, leading to an increase in systemic idarubicin concentrations. Renal impairment can affect the metabolism of idarubicin. The oral administration of idarubicin is therefore not recommended in patients with hepatic and/or renal impairment (see section 4.4) and idarubicin is contraindicated in patients with severe renal or hepatic impairment (see section 4.3).

Paediatric population:

Pharmacokinetic measurements taken from 7 paediatric patients receiving intravenous idarubicin hydrochloride at doses between 15 and 40 mg/m2 for 3 days showed that the median half-life of idarubicin was 8.5 hours (range: 3.6 – 26.4 hours). The active metabolite, idarubicinol, accumulated over the 3 days of treatment, has a median half-life of 43.7 hours (range: 27.8 – 131 hours). In another study, pharmacokinetic measurements taken from 15 paediatric patients receiving idarubicin hydrochloride orally at doses between 30 and 50 mg/m² for 3 days showed that the peak plasma concentration of idarubicin hydrochloride was 10.6 ng/ml (range: 2.7 – 16.7 ng/ml at the dose of 40 mg/m2). The median terminal half-life of idarubicin was 9.2 hours (range: 6.4 – 25.5 hours). A significant accumulation of idarubicinol was observed over the 3-day treatment period. The terminal half-life of idarubicin observed after intravenous administration was comparable to that observed after oral administration in paediatric patients.
In adults, after oral administration of 10 to 60 mg/m2 of idarubicin hydrochloride, the idarubicin hydrochloride was rapidly absorbed, with peak plasma concentrations of 4 to 12.65 ng/ml reached at 1 to 4 hours after administration. The terminal half-life was 12.7 ± 6 hours (mean ± SD). After the intravenous administration of idarubicin in adults, the terminal half-life was 13.9 ± 5.9 hours, and comparable to that observed after oral administration.
As the Cmax of idarubicin is comparable in children and adults after oral administration, absorption kinetics do not appear to be different in these two populations.
After both oral and intravenous administration, the elimination half-life values of idarubicin are different in children and adults:
Total body clearance values of idarubicin between 30 and 107.9 l/h/m² observed in adults are higher than the values ranging from 18 to 33 l/h/m² observed in the paediatric population. Although the volume of distribution of idarubicin is very high in both adults and children, suggesting that most of the medicine binds to tissues, the shorter elimination half-life and the lower total body clearance cannot be fully explained by an apparent volume of distribution lower in children than in adults.