title: A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer.
abstract: OBJECTIVE
  P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel.
  
  
  METHODS
  In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m(2)) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). (99m)Tc-sestamibi scanning and CD56(+) mononuclear cell rhodamine efflux assays were conducted to assess Pgp inhibition. In subsequent cycles, 75 mg/m(2) docetaxel was administered with 150 mg tariquidar every 3 weeks.
  
  
  RESULTS
  Forty-eight patients were enrolled onto the trial. Nonhematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56(+) cells and reduced (99m)Tc-sestamibi clearance from the liver. There was striking variability in basal sestamibi uptake; a 12% to 24% increase in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four partial responses (PR) were seen (4/48); 3 in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57%, and 67% by RECIST, and 1 PR in a patient with ovarian cancer.
  
  
  CONCLUSIONS
  Tariquidar is well tolerated, with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
authors.forename: Deborah
authors.initials: D
authors.lastname: Draper
authors.forename: Clara C
authors.initials: CC
authors.lastname: Chen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Aradhana M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; D043823:Taxoids; D000077143:Docetaxel; C402343:tariquidar