Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment, ATC code: V03AF02 Mechanism of action


The exact mechanism by which dexrazoxane exerts its cardioprotective effect has not been fully elucidated, however based on the available evidence the following mechanism has been suggested. The dose-dependent cardiotoxicity observed during anthracycline administration is due to anthracycline-induced iron-dependent free radical oxidative stress on the relatively unprotected cardiac muscle. Dexrazoxane, an analogue of EDTA (ethylene diamine tetra-acetic acid), is hydrolysed in cardiac cells to the ring-opened product ICRF- 198. Both dexrazoxane (ICRF-187) and ICRF-198 are capable of chelating metal ions. It is generally thought that they can provide cardioprotection by scavenging metal ions thus preventing the Fe3+-anthracycline complex from redox cycling and forming reactive radicals.

Clinical efficacy and safety

The evidence from clinical trials to date suggests increasing cardioprotective benefit from dexrazoxane as the cumulative anthracycline dose is increased.

Dexrazoxane does not protect against non-cardiac toxicities induced by anthracyclines.

The majority of controlled clinical studies were performed in patients with advanced breast cancer and employed a dosing ratio of dexrazoxane:doxorubicin of 20:1 or 10:1. In two clinical studies that used the higher dose ratio (one in breast cancer and one in small cell lung cancer) a higher rate of death was reported in the groups treated with dexrazoxane plus chemotherapy compared to those treated with chemotherapy alone or with placebo. The dose ratio was subsequently reduced to 10:1 in both studies, and no significant differences in survival were reported in patients treated at the lower dose ratio. However, a number of studies that used the higher dose ratio throughout have not reported any difference in survival.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
After intravenous administration to cancer patients, serum kinetics of dexrazoxane generally follow an open two-compartment model with first-order elimination. The maximum plasma concentration observed after a 12-15 minute infusion of 1000 mg/m2 is around 80 μg/ml with area under the plasma concentration-time curve (AUC) of 130 ± 27 mg.h/l. The plasma concentrations declined thereafter with an average half-life value of 2.2 ± 0.42 hours. The total body clearance of dexrazoxane in adults is estimated at 14.4 ± 2.8 l/h.

Distribution
The apparent volume of distribution is 44.0 ± 3.9 l, suggesting that dexrazoxane distributes mainly in the total body water. Plasma protein binding of dexrazoxane is low (2%) and it does not penetrate into the cerebrospinal fluid to a clinically significant extent.

Biotransformation and metabolism
Cardioxane and its metabolites were detected in the plasma and urine of animals and man.

Elimination
Urinary excretion plays an important role in the elimination of dexrazoxane. The total urinary excretion of unchanged dexrazoxane is in the order of 40%.

Special populations

Geriatric patients
No studies have been conducted in the elderly and dexrazoxane . Clearance may be reduced in elderly patients and patients with low creatinine clearance.

Hepatic impairment
No studies have been conducted in subjects with hepatic impairment.

Renal impairment
Compared with normal subjects (creatinine clearance (CLCR) >80 ml/min), exposure was 2-fold greater in subjects with moderate (CLCR of 30 to 50 ml/min) to severe (CLCR <30 ml/min) renal impairment.
Modeling suggested that equivalent exposure (AUC0-inf) could be achieved if dosing were reduced by 50% in subjects with CLCR less than 40 ml/min compared with control subjects (CLCR >80 ml/min).