Dexrazoxane

Dexrazoxane (Cardioxane®, Zinecard®), a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines.

As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer, regardless of whether the drug is given before the first dose of anthracycline or the administration is delayed until cumulative doxorubicin dose is ≥300 mg/m². The drug also appears to offer cardioprotection irrespective of pre-existing cardiac risk factors. Importantly, the antitumour efficacy of anthracyclines is unlikely to be altered by dexrazoxane use, although the drug has not been shown to improve progression-free and overall patient survival. At present, the cardioprotective efficacy of dexrazoxane in patients with childhood malignancies is supported by limited data. The drug is generally well tolerated and has a tolerability profile similar to that of placebo in cancer patients undergoing anthracycline-based chemotherapy, with the exception of a higher incidence of severe leukopenia (78% vs 68%; p < 0.01). Dexrazoxane is the only cardioprotective agent with proven efficacy in cancer patients receiving anthracycline chemotherapy and is a valuable option for the prevention of cardiotoxicity in this patient population

Dexrazoxane provides cardiac protection from anthracyclines primarily through the metal-chelating activity of its intracellular hydrolysis products in the myocardium. This activity involves chelation of free iron and iron bound in anthracycline complexes, thereby preventing the formation of cardiotoxic reactive oxygen radicals.

In animals treated with cardiotoxic doses of doxorubicin or epirubicin, the incidence of cardiac lesions was significantly reduced and the survival rate significantly increased compared with no dexrazoxane treatment. In animal models, dexrazoxane was more effective when administered immediately prior to, or simultaneously with, rather than after, the anthracycline. In addition, administration of dexrazoxane before the first cardiotoxic dose of doxorubicin was significantly more cardioprotective than delaying the dexrazoxane administration until the sixth doxorubicin dose.

The Pharmacokinetics of intravenous dexrazoxane appear to follow first-order elimination kinetics in a two-compartment model. The absorption kinetics of dexrazoxane are linear within a 6–900 mg/m² dose range. Tissue distribution of dexrazoxane is rapid, reaching equilibrium within 2–4 hours, with the highest concentrations of the parent drug and its final hydrolysis product being found in the liver and kidneys. Plasma protein binding is minimal. Dexrazoxane is enzymatically hydrolysed to its more active open-ring forms in the liver, kidney, heart, erythrocytes and leukocytes. Elimination is predominantly renal in the unchanged form. Distribution and elimination appear to be significantly greater in children than in adults.

The administration of dexrazoxane at recommended doses 15–30 minutes prior to doxorubicin or epirubicin does not significantly alter the pharmacokinetic properties of either drug.

Dexrazoxane demonstrated significant cardioprotection in women with advanced breast cancer receiving anthracycline chemotherapy. The incidence of anthracycline-induced cardiac events was significantly lower with (0–15%), than without (16–50%), dexrazoxane in all phase III trials. In three of six trials, the incidence of CHF was also significantly lower with (0–3%), than without (8–27%), dexrazoxane in both anthracycline-naive and -experienced patients.

In adults with small-cell lung carcinoma receiving doxorubicin and in those with soft tissue sarcomas (combined analysis of results in breast cancer patients) treated with high-dose epirubicin, dexrazoxane significantly reduced the incidence of anthracycline-induced cardiac events (including CHF in the latter patient group). Dexrazoxane provided effective short- and medium-term cardioprotection in patients (aged ≤24 years) who received anthracycline-based chemotherapy for childhood malignancies, including acute lymphoblastic leukaemia and various types of sarcoma; no long-term data are currently available.

According to two meta-analyses, dexrazoxane significantly reduces the relative risk of anthracycline-induced cardiotoxicity in cancer patients by 72–76% compared with no treatment and does not increase the relative risk of chemotherapy failure or decrease patient survival.

Dexrazoxane is a well tolerated drug with a tolerability profile similar to that of placebo in adult cancer patients receiving anthracycline-based chemotherapy, the difference being a significantly higher incidence of severe leukopenia with dexrazoxane. Limited data in children with malignancies receiving anthracyclines indicate relatively good tolerance of dexrazoxane in this patient population. In addition, dexrazoxane appears equally well tolerated when administered with doxorubicin at either 10: 1 or 20: 1 dosage ratios.