Development of LC-MS/MS method for the simultaneous analysis of the cardioprotective drug dexrazoxane and its metabolite ADR-925 in isolated cardiomyocytes and cell culture medium.

Dexrazoxane (DEX) is the only clinically used drug effective against anthracycline-induced cardiotoxicity and extravasation injury. However, the mechanism of its cardioprotective action still remains elusive. This paucity of comprehensive data is at least partially caused by the analytical difficulties associated with selective and sensitive simultaneous determination of the parent drug and its putative active metabolite ADR-925 in the relevant biological material. The aim of this study was to develop and validate the first LC-MS/MS method for simultaneous determination of DEX and ADR-925 in the isolated rat neonatal ventricular cardiomyocytes (NVCMs) and the cell culture medium. The analysis was performed on a Synergi Polar-RP column using the gradient profile of the mobile phase composed of 2mM ammonium formate and methanol. Electrospray ionization and ion trap mass analyzer were used as ionization and detection techniques, respectively. NVCMs were precipitated with methanol and the cell culture medium samples were diluted with the same solvent prior the LC-MS/MS analysis. The method was validated within the range of 4-80pmol/10(6) NVCMs and 7-70pmol/10(6) NVCMs for DEX and ADR-925, respectively, and at the concentrations of 8-100µM for both compounds in the culture cell medium. The practical applicability of this method was confirmed by the pilot analysis of NVCMs and the corresponding cell medium samples from relevant in vitro experiment. Hence, the LC-MS/MS method developed in this study represents a modern analytical tool suitable for investigation of DEX bioactivation inside the cardiomyocytes. In addition, the basic utility of the method for the analysis of DEX and ADR-925 in plasma samples was proved in a pilot experiment.

Pharmacokinetics of dexrazoxane in subjects with impaired kidney function.

Dexrazoxane is approved as a cardioprotective agent for use in female patients with breast cancer who are receiving doxorubicin. The effect of renal insufficiency on elimination is not known. The pharmacokinetics of dexrazoxane 150 mg/m(2), given as a 15-minute constant-rate intravenous infusion, were assessed in 24 men and women with varying degrees of renal function in a single-dose, open-label, parallel-group study. Blood and urine samples were measured by a validated liquid chromatography/mass spectrometry assay. Dexrazoxane pharmacokinetic parameters were derived by standard noncompartmental methods. The effect of kidney function and effect of body surface area on the pharmacokinetics of dexrazoxane were analyzed using linear and nonlinear regression in the SPSS statistical program. Dexrazoxane clearance is decreased in subjects with kidney dysfunction. Compared with normal subjects (creatinine clearance [CL(CR)] >80 mL/min), mean area under the concentration curve from time 0 to infinity (AUC(0-inf)) was 2-fold greater in subjects with moderate (CL(CR) 30-50 mL/min) to severe (CL(CR) <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC(0-inf)) could be achieved if dosing were reduced by 50% in subjects with CL(CR) less than 40 mL/min compared with control subjects (CL(CR) >80 mL/min). Modeling study results suggested that equivalent exposure could be achieved if dosing was halved in subjects with CL(CR) less than 40 mL/min compared with controls.

Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy.

Anthracycline-induced cardiomyopathy is a major problem in anti-cancer therapy. The only approved agent for alleviating this serious dose limiting side effect is ICRF-187 (dexrazoxane). The current thinking is that the ring-opened hydrolysis product of this agent, ADR-925, which is formed inside cardiomyocytes, removes iron from its complexes with anthracyclines, hereby reducing the concentration of highly toxic iron-anthracycline complexes that damage cardiomyocytes by semiquinone redox recycling and the production of free radicals. However, the 2 carbon linker ICRF-187 is also is a catalytic inhibitor of topoisomerase II, resulting in the risk of additional myelosuppression in patients receiving ICRF-187 as a cardioprotectant in combination with doxorubicin. The development of a topoisomerase II-inactive iron chelating compound thus appeared attractive. In the present paper we evaluate the topoisomerase II-inactive 3 carbon linker bisdioxopiperazine analog ICRF-161 as a cardioprotectant. We demonstrate that this compound does chelate iron and protects against doxorubicin-induced LDH release from primary rat cardiomyocytes in vitro, similarly to ICRF-187. The compound does not target topoisomerase II in vitro or in cells, it is well tolerated and shows similar exposure to ICRF-187 in rodents, and it does not induce myelosuppression when given at high doses to mice as opposed to ICRF-187. However, when tested in a model of chronic anthracycline-induced cardiomyopathy in spontaneously hypertensive rats, ICRF-161 was not capable of protecting against the cardiotoxic effects of doxorubicin. Modulation of the activity of the beta isoform of the topoisomerase II enzyme by ICRF-187 has recently been proposed as the mechanism behind its cardioprotection. This concept is thus supported by the present study in that iron chelation alone does not appear to be sufficient for protection against anthracycline-induced cardiomyopathy.

Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity.

Dexrazoxane is a derivative of the powerful metal-chelating agent ethyl enediamine tetra acetic acid. Its cardioprotective effect is thought to be due to its ability to chelate iron and reduce the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. Preclinical studies have confirmed that dexrazoxane has significant activity as a cardioprotective agent against anthracycline-induced cardiotoxicity. Dexrazoxane is well-tolerated, with myelosuppression being the dose-limiting toxicity in Phase I trials. The cardioprotective utility of dexrazoxane has been further illustrated in a number of randomized trials. In addition no significant difference in survival has been observed between the dexrazoxane and control arms of these trials but, in one, a significantly lower response rate was observed in the dexrazoxane compared to placebo arm. Further trials are required to evaluate the efficacy of dexrazoxane in hematological malignancies as well as the adjuvant treatment of breast cancer. Its use in the paediatric setting and in the management of elderly patients with cardiac comorbidity also requires investigation. Recently, interest has focused on the use of dexrazoxane as an antidote for anthracycline extravasation. In addition the general cytoprotective activity of this drug requires further assessment, as well as selectivity in this context.

The dihydroorotase inhibitor 5-aminoorotic acid inhibits the metabolism in the rat of the cardioprotective drug dexrazoxane and its one-ring open metabolites.

Dexrazoxane (ICRF-187) is clinically used as a doxorubicin cardioprotective agent and to prevent anthracycline extravasation injury. It may act by preventing iron-based oxygen free radical damage through the iron-chelating ability of its metabolite N,N'-[(1S)-1-methyl-1,2-ethanediyl]bis[(N-(2-amino-2-oxoethyl)]glycine (ADR-925). Dexrazoxane undergoes an initial metabolism to its two one-ring open intermediates [N-(2-amino-2-oxoethyl)-N-[(1S)-2-(3,5-dioxo-1-piperazinyl)-1-methylethyl]glycine (B) and N-(2-amino-2-oxoethyl)-N-[(2S)-2-(3,5-dioxo-1-piperazinyl)propyl]glycine (C)] and is then further metabolized to its presumably active metal-chelating form ADR-925. We previously showed that the first ring opening reaction is catalyzed by dihydropyrimidinase and the second by dihydroorotase (DHOase), but not vice versa. To determine whether DHOase was important in the metabolism of dexrazoxane, its metabolism and that of B and C to ADR-925 were measured in rats that were pretreated with the DHOase inhibitor 5-aminoorotic acid. In rats pretreated with 5-aminoorotic acid the area-under-the-curve concentration of ADR-925 was reduced 5.3-fold. In rats treated with a mixture of B and C, the maximum concentration of ADR-925 in the plasma was significantly decreased in rats pretreated with 5-aminoorotic acid, which indicates that DHOase directly metabolized B and C. Both heart and liver tissue levels of ADR-925 in rats were also greatly reduced by pretreatment with 5-aminoorotic acid. Together these results indicate that the metabolism of dexrazoxane and of B and C is mediated by DHOase. These results provide a mechanistic basis for the antioxidant cardioprotective activity of dexrazoxane.

Dexrazoxane use in the prevention of anthracycline extravasation injury.

Accidental extravasation injury from the use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin can be a serious complication of their use. As yet, there is little consensus on the way that anthracycline extravasation injury should be clinically managed. Dexrazoxane, which is currently clinically used to reduce doxorubicin-induced cardiotoxicity, has also been shown in preclinical studies to be highly efficacious in preventing anthracycline-induced extravasation injury. Several clinical case reports of dexrazoxane for this use have also indicated positive outcomes. There are currently two multicenter Phase II/III clinical trials underway. Dexrazoxane is a prodrug analog of the metal chelator EDTA that most likely acts by removing iron from the iron-doxorubicin complex, thus preventing formation of damaging reactive oxygen species.

Metabolism of the one-ring open metabolites of the cardioprotective drug dexrazoxane to its active metal-chelating form in the rat.

Dexrazoxane (ICRF-187) is clinically used as a doxorubicin cardioprotective agent and may act by preventing iron-based oxygen free radical damage through the iron-chelating ability of its fully hydrolyzed metabolite ADR-925 (N,N'-[(1S)-1-methyl-1,2-ethanediyl]-bis[(N-(2-amino-2-oxoethyl)]glycine). Dexrazoxane undergoes initial metabolism to its two one-ring open intermediates and is then further metabolized to its active metal ion-binding form ADR-925. The metabolism of these intermediates to the ring-opened metal-chelating product ADR-925 has been determined in a rat model to identify the mechanism by which dexrazoxane is activated. The plasma concentrations of both intermediates rapidly decreased after their i.v. administration to rats. A maximum concentration of ADR-925 was detected 2 min after i.v. bolus administration, indicating that these intermediates were both rapidly metabolized in vivo to ADR-925. The kinetics of the initial appearance of ADR-925 was consistent with formation rate-limited metabolism of the intermediates. After administration of dexrazoxane or its two intermediates, ADR-925 was detected in significant levels in both heart and liver tissue but was undetectable in brain tissue. The rapid rate of metabolism of the intermediates was consistent with their hydrolysis by tissue dihydroorotase. The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These studies showed that the two one-ring open metabolites of dexrazoxane were rapidly metabolized in the rat to ADR-925, and thus, these results provide a mechanism by which dexrazoxane is activated to its active metal-binding form.

Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy.

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 > or =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.

Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies.

PURPOSE: Dexrazoxane administration prior to short infusion doxorubicin prevents anthracycline-related heart damage. Since delivery of doxorubicin by 96-h continuous intravenous infusion also reduces cardiac injury, we studied delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous infusion. METHODS: Patients with advanced malignancies received tandem cycles of concurrent 96-h infusions of dexrazoxane 500 mg/m2 and doxorubicin 165 mg/m2, and 24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5 microg/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 microl(-1). Plasma samples were analyzed for dexrazoxane and doxorubicin concentrations. RESULTS: Ten patients were enrolled; eight patients had measurable disease. Two partial responses were observed in patients with soft-tissue sarcoma. The median number of days of granulocytopenia (<500 microl(-1)) was nine and of platelet count <20,000 microl(-1) was seven. Six patients received a single cycle because of progression (one), stable disease (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction (two). Principal grade 3/4 toxicities included hypotension (two), anorexia (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with documented infection (three). One death from neutropenic sepsis occurred. Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged from 59.1 to 106.9 nM. CONCLUSIONS: These results suggest that tandem cycles of concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be administered with minimal cardiac toxicity, and have activity in patients with recurrent sarcomas. However, significant non-cardiac toxicities indicate that the cardiac sparing potential of this approach would be maximized at lower dose levels of doxorubicin.

Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane.

Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.

The doxorubicin-cardioprotective drug dexrazoxane undergoes metabolism in the rat to its metal ion-chelating form ADR-925.

PURPOSE: Dexrazoxane is clinically used as a doxorubicin-cardioprotective agent and may act by preventing iron-based oxygen free-radical damage through the iron-chelating ability of ADR-925. The metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its rings-opened metal-chelating product ADR-925 was determined in a rat model in order to identify the mechanism by which dexrazoxane acts. METHODS: A new fluorescence detection flow injection assay utilizing the metal-chelating dye calcein was developed to detect ADR-925 in blood plasma. Dexrazoxane and its one-ring open metabolites were determined by HPLC. RESULTS: ADR-925 was detected within 5 min of i.v. administration of dexrazoxane to rats, suggesting that dexrazoxane is rapidly metabolized in vivo. The plasma concentrations of ADR-925 exceeded those of both one-ring open intermediates at 30 min and those of dexrazoxane by 80 min and reached a maximum at 80 min, and then slowly decreased. CONCLUSIONS: The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results indicate that the one-ring open dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.

Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies.

Dexrazoxane is a bidentate chelator of divalent cations. Pretreatment with short infusions of dexrazoxane prior to bolus doxorubicin has been shown to lessen the incidence and severity of anthracycline-associated cardiac toxicity. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular retention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-h infusion of dexrazoxane was performed. Dexrazoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocyte-colony stimulating factor at a dose of 5 microg/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and analyzed for dexrazoxane by high-performance liquid chromatography. Urine collections were performed at baseline and during the infusion to determine the renal clearance of dexrazoxane and the excretion rate of divalent cations. Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m(2)/day. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 patients treated at 250 mg/m(2)/day, grade 3 thrombocytopenia and grade 4 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, grade 4 diarrhea and grade 3 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, and grade 3 hypertension in 1 patient treated at 166.25 mg/m(2)/day. Steady-state dexrazoxane levels ranged from 496 microg/l (2.2 microM) to 1639 microg/l (7.4 microM). Dexrazoxane plasma CL(ss) and elimination t(1/2) were 7.2 +/- 1.6 l/h/m(2) and 2.0 +/- 0.8 h, respectively. The mean percentage of administered dexrazoxane recovered in the urine at steady state was 30% (range, 10-66%). Urinary iron and zinc excretion during the dexrazoxane infusion increased in 12 of 18 and 19 of 19 patients by a median of 3.7- and 2.4-fold, respectively. These results suggest that dexrazoxane as a 96-h infusion can be safely administered with granulocyte-colony stimulating factor at doses that achieve plasma levels that have been demonstrated previously to inhibit topoisomerase II activity and to induce apoptosis in vitro. Additional studies will be required to determine whether the combination of continuous infusions of dexrazoxane and doxorubicin would provide enhanced cardioprotection compared with the currently recommended bolus or short infusion schedules.

Stereoselective metabolism of dexrazoxane (ICRF-187) and levrazoxane (ICRF-186).

A chiral HPLC method has been developed to separate razoxane (ICRF-159) in blood plasma into its enantiomers dexrazoxane (ICRF-187) and levrazoxane (ICRF-186). Dexrazoxane is clinically used as a doxorubicin cardioprotective agent and little is known of its in vivo metabolism. After intravenous administration of 20 mg/kg of razoxane to rats, the razoxane was eliminated from the plasma with a half-time of approximately 20 min. The levrazoxane:dexrazoxane ratio continuously increased with time to a value of 1.5 at 150 min, indicating that dexrazoxane is metabolized faster than levrazoxane. These results, confirmed with studies on liver supernatants, are consistent with the hypothesis that dihydropyrimidine amidohydrolase in the liver and kidney is responsible for the preferential metabolism of dexrazoxane in the rat compared to levrazoxane. It is possible that on a dose-per-dose basis marginally higher therapeutic levels of levrazoxane might be achieved in the heart tissue for a longer time compared to dexrazoxane due to dihydropyrimidine amidohydrolase-based metabolism in the liver and kidney. However, given the relatively small difference in elimination of the two enantiomers, it would be difficult to predict from this study whether or not dexrazoxane or levrazoxane might be more efficacious in reducing cardiotoxicity.

Relative plasma levels of the cardioprotective drug dexrazoxane and its two active ring-opened metabolites in the rat.

A postcolumn derivatization reversed-phase high-pressure liquid chromatography method has been developed to detect and separate the one-ring open intermediates of dexrazoxane (ICRF-187) in blood plasma. Dexrazoxane is clinically used as a doxorubicin cardioprotective agent and may act by preventing iron-based oxygen-free radical damage through the iron-chelating ability of its one-ring open intermediates and its fully rings opened hydrolysis product ADR-925. Little is known of the in vivo metabolism of dexrazoxane to its one-ring open intermediates, which may be two of the active forms of dexrazoxane. The one-ring open intermediates were detected within 5 min of i.v. administration of dexrazoxane to rats, suggesting that dexrazoxane is rapidly metabolized in vivo. The plasma concentrations of the one-ring open intermediates varied from 4 to 9% and 6 to 24% of the dexrazoxane concentrations at 5 and 120 min, respectively. The relatively small changes in the levels of the one-ring open intermediates with time suggest that a dynamic steady state is occurring. The ratio of the concentrations of the two one-ring open intermediates was similar to that previously seen for the in vitro dihydropyrimidine amidohydrolase-catalyzed hydrolysis of dexrazoxane. These results are consistent with the hypothesis that dihydropyrimidine amidohydrolase in the liver and kidney is responsible for the metabolism of dexrazoxane in the rat.

Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy.

UNLABELLED: Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20:1 or 10:1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a > or = 2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose > or = 300 mg/m2. It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaematological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a cost-effective agent in women with advanced breast cancer, they require confirmation. CONCLUSIONS: Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen.

Clinical pharmacology of dexrazoxane.

Dexrazoxane is a synthetic bisdiketopiperazine two-ringed compound which hydrolyzes to an EDTA analog. These rings undergo intracellular hydrolysis to form the single and double (ICRF-198) chelating forms of the compound by both enzymatic and non-enzymatic catalysis. These dexrazoxane metabolites are efficient at stripping the cations from the iron:anthracycline complex. The disruption of the complex prevents the oxidative damage from free radicals promoted by this anthracycline complex. Pharmacologic studies of single agent dexrazoxane (originally studied as an antineoplastic agent) demonstrates an alpha half-life of approximately 30 minutes and a beta half-life of 2 to 4 hours. When given in combination with anthracyclines (e.g. doxorubicin or epirubicin) the pharmacokinetics of dexrazoxane are unchanged. Additional studies of anthracycline metabolism when given in combination with dexrazoxane, both in single arm and randomized cross-over studies, have generally shown no change in anthracycline metabolism, including pharmacokinetic parameters of alpha, beta, and gamma half-lives, area-under-the-curve, or clearance. There is no pharmacokinetic interaction of dexrazoxane on anthracycline metabolism and, therefore, pharmacokinetics cannot account for the cardioprotective effects described for dexrazoxane.

Antineoplastic activity of continuous exposure to dexrazoxane: potential new role as a novel topoisomerase II inhibitor.

Although originally developed as an antitumor agent in the 1970s, dexrazoxane (DEX) is currently used as a cardioprotective agent in combination with doxorubicin (DOX). Due to concerns about anthracycline-induced cardiotoxicity at higher cumulative doses, many investigators have chosen to administer DOX by prolonged infusion. Therefore, with the ultimate goal of combining infusional DEX and DOX, we performed a phase I study of intravenous DEX alone as a 96-hour infusion. Surprisingly, the maximum tolerated dose of DEX identified in this study was 10- to 15-fold lower than previously determined using different schedules of administration. Results of pharmacokinetic studies in support of the trial have found that steady-state DEX plasma concentrations in the range of 4 to 5 micromol/L can be achieved safely. Because previous experiments have explored the ability of DEX to inhibit the catalytic activity topoisomerase II at low micromolar concentrations and due to a lack of in vitro cytotoxicity data for long-term exposures, we performed further laboratory studies to provide a context for our pharmacokinetic findings. As a result of these correlative studies, we have found that prolonged exposures to DEX are cytotoxic to human leukemic cells at concentrations that are clinically achievable.

Dose-independent pharmacokinetics of the cardioprotective agent dexrazoxane in dogs.

A randomized, four-way cross-over design was used to assess the disposition of the cardioprotective agent, dexrazoxane, in four male beagle dogs following single I.V. administration of 10, 25, 50, and 100 mg kg-1 doses. Parent drug was quantified in plasma and urine with a validated high-pressure liquid chromatographic-electrochemical assay. A two-compartment open model adequately described the dexrazoxane plasma concentration versus time data. The terminal half-life ranged between 1.1 and 1.3 h and the apparent steady-state distribution volume was 0.67 L kg-1. The systemic clearance (CL) ranged from 10.3 to 11.5 mL min-1 kg-1, while estimates of renal clearance approximated the glomerular filtration rate (GFR approximately 3.2-4.9 mL min-1 kg-1). Over the dose range evaluated, CL was dose independent (ANOVA, p = 0.33), while concentration at the end of infusion (Cend) and the area under the concentration versus time curve (AUC) were directly proportional to the dose (r > 0.999). The blood cell to plasma partitioning ratio was approximately 0.517 and drug was essentially unbound to plasma proteins (fu approximately 0.95). Dexrazoxane appeared to be subject to low organ extraction, since the hepatic and renal drug extraction ratios were on the order of 0.228 +/- 0.054 and 0.184 +/- 0.024, respectively. These results suggest a relatively small drug distribution space (approximately equal to total-body water) and low tissue and plasma protein binding. In light of the low plasma protein binding and extraction ratio exhibited by dexrazoxane, metabolic capacity and renal function would appear to be the predominant variables affecting the CL of this drug. The constancy of the half-life, CL, and VSS with increasing dose indicates dose-independent disposition for dexrazoxane. Thus a linear increase in the systemic exposure can be predicted over this dose range.

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.

PURPOSE: We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients. METHODS: Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities. RESULTS: Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity. CONCLUSION: ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.