title: Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer.
abstract: OBJECTIVE
  This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial.
  
  
  METHODS
  Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m(2)) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored.
  
  
  RESULTS
  Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03).
  
  
  CONCLUSIONS
  Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.
authors.affiliation: Mary Babb Randolph (MBR) Cancer Center, West Virginia University, PO Box 9300, Morgantown, WV, 26506, USA.
authors.forename: Islam R
authors.initials: IR
authors.lastname: Younis
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.forename: Terence J
authors.initials: TJ
authors.lastname: McManus
authors.forename: Herbert
authors.initials: H
authors.lastname: Hurwitz
authors.forename: Patricia
authors.initials: P
authors.lastname: Creel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: Jing Jie
authors.initials: JJ
authors.lastname: Yu
authors.forename: Kristina
authors.initials: K
authors.lastname: Bacon
authors.forename: Gerald
authors.initials: G
authors.lastname: Hobbs
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000077868:Atrasentan; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; D043823:Taxoids; D000077143:Docetaxel; D000077868:Atrasentan