TY - JOUR
T1 - Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin
AU - Hochster, Howard
AU - Liebes, Leonard
AU - Wadler, Scott
AU - Oratz, Ruth
AU - Wernz, James C.
AU - Meyers, Marleen
AU - Green, Michael
AU - Blum, Ronald H.
AU - Speyer, James L.
N1 - Funding Information:
Received May 14, 1992; revised August 12, 1992; accepted August 21, 1992. Supported in part by a grant from Adria Laboratories, Columbus, Ohio; by Public Health Service grants CA-16087 (National Cancer Institute) and CRC-RR-99 (National Center for Research Resources), National Institutes of Health, Department of Health and Human Services; and by American Cancer Society research grant CH-479. Preliminary results of this study have previously been reported at the 26th (Washington, D.C., May 1990) and 27th (Houston, Tex., May 1991) meetings of the American Society of Clinical Oncology. H. Hochster, L. Liebes, R. Oratz, J. C. Wernz, M. Meyers, R. H. Blum, J. L. Speyer, Kaplan Cancer Center and the Division of Medical Oncology, New York University Medical Center, New York, N.Y. S. Wadler, The Albert Einstein Cancer Center and the Montefiore Hospital, The Bronx, N.Y. M. Green, Royal Melbourne Hospitals, Australia. We thank Susan Alba, Joan Sorich, and Rosa Cendano for nursing care and follow-up; Sandra Mendoza, Raghavan Sampathkumaran, and Daniel Orellana for their long hours in the laboratory and at the computer performing pharmacokinetic analyses; and Margaret Nixdorf for preparation of the manuscript. 'Correspondence to: Howard Hochster, M.D., Kaplan Cancer Center, Division of Medical Oncology, New York University Medical Center, 530 First Ave., New York, NY 10016.
PY - 1992/11/18
Y1 - 1992/11/18
N2 - 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]
AB - 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]
UR - http://www.scopus.com/inward/record.url?scp=0026496068&partnerID=8YFLogxK
U2 - 10.1093/jnci/84.22.1725
DO - 10.1093/jnci/84.22.1725
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C2 - 1433357
AN - SCOPUS:0026496068
SN - 0027-8874
VL - 84
SP - 1725
EP - 1730
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 22
ER -
