Article

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

Department of Medicine, Section of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Clinical Cancer Research (impact factor: 7.74). 06/2004; 10(10):3265-72. DOI:10.1158/1078-0432.CCR-03-0644 pp.3265-72
Source: PubMed

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

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Keywords

40 patients
 
48 h i.v. dosing schedule
 
9 cohorts
 
cohort-dose escalation manner
 
demonstrable clinical significance
 
Dose escalation proceeded
 
dose-limiting toxicity
 
Doxorubicin doses
 
enhanced leukopenia
 
exceeded 500 mg
 
first cycle
 
higher doses
 
maximal doses
 
maximal P-glycoprotein inhibition
 
modest decrease
 
natural killer cells
 
P-glycoprotein function
 
Pharmacokinetic analysis
 
potent P-glycoprotein modulator
 
subsequent cycles
 

Alan Sandler