title: Fulvestrant decreases anastrozole drug concentrations when taken concurrently by patients with metastatic breast cancer treated on SWOG study S0226.
abstract: In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n = 349) was superior to anastrozole alone (n = 345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant.
  
  
  
  Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6 and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model.
  
  
  
  A total of 483 anastrozole concentration measurements were included, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the combination arm. The mean anastrozole concentration in the combination arm was significantly lower than that in the anastrozole alone arm at each sample collection time (all P < 0.01) and in the mixed effects model (an estimated difference of 9.85 ng ml(-1) (95% CI 5.69, 14.00 ng ml(-1) ), P < 0.001).
  
  
  
  A significant pharmacokinetic drug interaction was detected, in which the addition of fulvestrant to anastrozole treatment decreased the trough anastrozole concentration. Further research is needed to verify whether this interaction affects treatment efficacy and to determine the pharmacological mechanism by which this interaction occurs.
authors: College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors: Daniel L
authors: DL
authors: Hertz
authors: SWOG Statistical Center, Seattle, WA, USA.
authors: William E
authors: WE
authors: Barlow
authors: University of Michigan, School of Public Health, Ann Arbor, MI, USA.
authors: Kelley M
authors: KM
authors: Kidwell
authors: Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.
authors: Kathy S
authors: KS
authors: Albain
authors: London Health Sciences Center/National Cancer Institute of Canada Clinical, Trials Group, London, ON, Canada.
authors: Ted A
authors: TA
authors: Vandenberg
authors: Wichita NCORP, Wichita, KS, USA.
authors: Shaker R
authors: SR
authors: Dakhil
authors: Kaiser Permanente NCORP, Portland, OR, USA.
authors: Nagendra R
authors: NR
authors: Tirumali
authors: Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors: Robert B
authors: RB
authors: Livingston
authors: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
authors: Julie
authors: J
authors: Gralow
authors: Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors: Daniel F
authors: DF
authors: Hayes
authors: University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: University of California Irvine Medical Center, Chao Family Comprehensive, Cancer Center, Orange, CA, USA.
authors: Rita S
authors: RS
authors: Mehta
authors: Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors: James M
authors: JM
authors: Rae
mesh_terms: D000077384:Anastrozole; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D009570:Nitriles; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol
keywords: anastrozole; breast cancer; drug interaction; fulvestrant; pharmacokinetics