Dexrazoxane

Two pharmacodynamic properties of dexrazoxane are described in the literature:

1. Prevention of anthracycline cardiotoxicity, and
2. Antineoplastic action

Dexrazoxane has two major mechanisms of action:

1. Chelation of iron, especially through its ring-opened metabolite thus reducing the irondependent oxidative stress causing anthracycline-induced cardiotoxicity.
2. Inhibition of topoisomerase II.

It is not known to what extent each of these mechanisms contributes to the preventive effect on tissue destruction following anthracycline extravasation.

The chelating property is probably also responsible for an increased urinary excretion of iron and zinc and a decreased serum concentration of calcium as described in a few studies.

Dexrazoxane must only be administered intravenously.

Distribution

Bibliographical data demonstrate that serum kinetics of dexrazoxane after intravenous administration follow an open two-compartment model independent of schedule and dose. The apparent volumes of distribution are 0.13-1.3 l/kg (median 0.49 l/kg). Volume of distribution is independent of dose. AUCs were dose-proportional. Tissue distribution is rapid, with the highest levels of unchanged parent compound and hydrolysed product appearing in liver and kidneys. About 2% of dexrazoxane is protein-bound.

Biotransformation

Dexrazoxane undergoes intracellular hydrolysis first to its two one-ring open intermediates (B and C) and then to the two-ring opened form (ADR-925) which has a structure similar to EDTA and is a strong chelator of iron and divalent cations as calcium ions.

Elimination

Dexrazoxane displays biphasic elimination kinetics. Initial elimination half lives (alpha) are 0.18-1 h (median 0.34 h) and terminal elimination half lives 1.9-9.1 h (median 2.8 h). Total urinary recovery of unchanged dexrazoxane is 34-60%. Systemic clearance is independent of dose. The pharmacokinetics of the metabolites is derived from a single study with five patients. The mean elimination half-lives of the one-ring opened metabolite B and metabolite C are 0.9-3.9 h (n=5) and 0.5-0.8 h (n=3) respectively. The elimination half-life of the two-ring opened metabolite ADR-925 is not given in literature. ADR-925 is reported to increase three-fold within 15 min after infusion of 1500 mg/m² and remain relatively constant on a plateau for 4 hours and then decreased to about half at 24 hours.

In-vitro studies on dexrazoxane in human microsomes have shown high stability of dexrazoxane indicating that major metabolism via cytochrome P450 is unlikely.

There is insufficient data available to draw any definite conclusions regarding intrinsic pharmacokinetic factors such as age, gender, race and weight. Inter- and intra-individual pharmacokinetic variabilities have not been studied systematically. Based on a limited number of patients, interindividual variability calculated as the coefficient of variation (CV ) was estimated to be approximately 30 for the main pharmacokinetic parameters.

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. Modelling suggested that equivalent exposure (AUC_0-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).

Pharmacokinetics in patients with extravasations

Clinical trial TT04 was conducted on 6 female patients undergoing treatment for anthracycline extravasations. The aim was to examine the pharmacokinetics of a 3-day dosing regimen of dexrazoxane and its efficacy in patients for anthracycline extravasation. The systemic clearances were similar between day 1 (9.9 L/h ± 3.1) and day 2 (11.1 L/h ± 4.5), and did not differ from those reported in the literature. The steady-state volume of distribution of dexrazoxane was 30.5 L ± 11.1 for day 1 and 35.8 L ± 19.7 for day 2. The terminal elimination half-life was consistent throughout days 1-3 (2.1-2.2 h). The mean AUC_0-24 values for day 1 and day 2 were comparable with each other, and the AUC_0-last at day 3 was approximately half that of the first two days, suggesting that the pharmacokinetics of dexrazoxane are dose-dependent. The overall ranges and mean of AUC_0-24 between days were very similar; it does not appear that there is any significant accumulation of dexrazoxane.

Repeat-dose toxicity studies with dexrazoxane have shown that primary target organs were tissues that undergo rapid cell division: bone marrow, lymphoid tissue, testes and digestive tract. Myelosuppression is thus common. The apparent effects were greater during chronic than acute administration. The toxicity in combination with doxorubicin was additive and not synergistic. Dexrazoxane has been shown to possess mutagenic activity. The carcinogenic potential of dexrazoxane has not been investigated, however, razoxane (the racemic mixture of dexrazoxane and levrazoxane) has been reported to be associated with the development of malignancies in mice (lymphoid neoplasms) and rats (uterine carcinomas) after administration for a prolonged period of time. Both of these effects are expected for this class of compound.

There are limited fertility data from animal studies available, but testicular changes were observed in rats and rabbits following repeat dosing.

The related razoxane has been demonstrated to be embryotoxic in mice, rats and rabbits and teratogenic in rats and mice.

When mice with experimental daunorubicin extravasation were treated with dexrazoxane systemically combined with topical treatment with DMSO on the daunorubicin-affected skin area, 67% of the mice developed small skin wounds, whereas dexrazoxane treatment alone completely prevented the daunorubicin-induced skin necrosis in another group of mice. Thus, dimethylsulfoxide (DMSO) should not be used in patients who are administered dexrazoxane to treat anthracycline extravasation.