A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy.

Abstract

PURPOSE:

Our intention was to (a) to investigate the safety and tolerability of a potent P-glycoprotein modulator, zosuquidar trihydrochloride (LY335979), when administered i.v. alone or in combination with doxorubicin, (b) to determine the pharmacokinetics of zosuquidar and correlate exposure to inhibition of P-glycoprotein function in a surrogate assay, and (c) to compare the pharmacokinetics of doxorubicin in the presence and absence of zosuquidar.

PATIENTS AND METHODS:

Patients with advanced malignancies who provided written informed consent received zosuquidar and doxorubicin administered separately during the first cycle of therapy and then concurrently in subsequent cycles. Zosuquidar was given i.v. over 48 h in a cohort-dose escalation manner until the occurrence of dose-limiting toxicity or protocol specified maximum exposure. Doxorubicin doses of 45, 60, 75 mg/m(2) were administered during the course of the trial.

RESULTS:

Dose escalation proceeded through 9 cohorts with a total of 40 patients. The maximal doses administered were 640 mg/m(2) of zosuquidar and 75 mg/m(2) of doxorubicin. No dose-limiting toxicity of zosuquidar was observed. Pharmacokinetic analysis revealed that, in the presence of zosuquidar at doses that exceeded 500 mg, there was a modest decrease in clearance (17-22%) and modest increase in area under the curve (15-25%) of doxorubicin. This change was associated with an enhanced leukopenia and thrombocytopenia but was without demonstrable clinical significance. The higher doses of zosuquidar were associated with maximal P-glycoprotein inhibition in natural killer cells.

CONCLUSION:

Zosuquidar can be safely coadministered with doxorubicin using a 48 h i.v. dosing schedule.

• Authors: Alan Sandler, Michael Gordon, Dinesh P De Alwis, Isabelle Pouliquen, Lisa Green, Phil Marder, Ajai Chaudhary, Karen Fife, Linda Battiato, Christopher Sweeney, Christopher Jordan, Michael Burgess, Christopher A Slapak
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 10 Pg. 3265-72 (May 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15161679 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Dibenzocycloheptenes
• Quinolines
• Doxorubicin
• zosuquidar trihydrochloride

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Area Under Curve
• Cohort Studies
• Dibenzocycloheptenes (administration & dosage, pharmacokinetics)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage)
• Drug Resistance, Multiple
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Quinolines (administration & dosage, pharmacokinetics)
• Time Factors