Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin

Howard Hochster*, Leonard Liebes, Scott Wadler, Ruth Oratz, James C. Wernz, Marleen Meyers, Michael Green, Ronald H. Blum, James L. Speyer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. Purpose: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. Methods: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). Results: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10: 1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 ± 18.3 (mean ± SD) hours; the area under the curve for plasma concentration of drug × time (AUC) was 1.74 ± 0.40 (μg/mL) × hour. Total-body clearance was 598 ± 142 mL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 ± 0.30 hours and 4.16 ± 2.94 hours, respectively. Total-body clearance was 111 ± 87 mL/m2 per minute (N = 18); AUC was linear (r2 =.92), and the clearance rate was constant (r2 =.18) from 60 to 900 mg/m2. Conclusions: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10: 1 to 12.5: 1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. Implications: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies. [J Natl Cancer Inst 84: 1725-1730, 1992]

Original languageEnglish
Pages (from-to)1725-1730
Number of pages6
JournalJournal of the National Cancer Institute
Issue number22
StatePublished - 18 Nov 1992
Externally publishedYes


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