title: 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: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Zosuquidar can be safely coadministered with doxorubicin using a 48 h i.v. dosing schedule.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Sandler
authors.forename: Michael
authors.initials: M
authors.lastname: Gordon
authors.forename: Dinesh P
authors.initials: DP
authors.lastname: De Alwis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pouliquen
authors.forename: Lisa
authors.initials: L
authors.lastname: Green
authors.forename: Phil
authors.initials: P
authors.lastname: Marder
authors.forename: Ajai
authors.initials: A
authors.lastname: Chaudhary
authors.forename: Karen
authors.initials: K
authors.lastname: Fife
authors.forename: Linda
authors.initials: L
authors.lastname: Battiato
authors.forename: Christopher
authors.initials: C
authors.lastname: Sweeney
authors.forename: Christopher
authors.initials: C
authors.lastname: Jordan
authors.forename: Michael
authors.initials: M
authors.lastname: Burgess
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Slapak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D003986:Dibenzocycloheptenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; D004317:Doxorubicin; C095179:zosuquidar trihydrochloride