title: Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin.
abstract: 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.
  
  
  OBJECTIVE
  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 x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/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 microL/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Kaplan Cancer Center, New York, N.Y.
authors.forename: H
authors.initials: H
authors.lastname: Hochster
authors.forename: L
authors.initials: L
authors.lastname: Liebes
authors.forename: S
authors.initials: S
authors.lastname: Wadler
authors.forename: R
authors.initials: R
authors.lastname: Oratz
authors.forename: J C
authors.initials: JC
authors.lastname: Wernz
authors.forename: M
authors.initials: M
authors.lastname: Meyers
authors.forename: M
authors.initials: M
authors.lastname: Green
authors.forename: R H
authors.initials: RH
authors.lastname: Blum
authors.forename: J L
authors.initials: JL
authors.lastname: Speyer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D011929:Razoxane / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D011929:Razoxane; D004317:Doxorubicin