title: Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer.
abstract: Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of anastrozole and anastrozole metabolites. There were large interindividual variations in plasma anastrozole and anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58-45.2 and 0.635-97.0 pg/mL, respectively). E1 conjugates after anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50-2,990 pg/mL). Two patients seemed to extensively metabolize anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to "individualize" therapy with this drug.
authors.affiliation: Division of Medical Oncology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. ingle.james@mayo.edu
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Aman U
authors.initials: AU
authors.lastname: Buzdar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: Anthony
authors.initials: A
authors.lastname: Batzler
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robson
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Randy A
authors.initials: RA
authors.lastname: Weintraub
authors.forename: Clark V
authors.initials: CV
authors.lastname: Williard
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D001943:Breast Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000737:chemistry; D004970:Estrone / Q000737:chemistry; D005260:Female; D006801:Humans; D008875:Middle Aged; D009570:Nitriles / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000737:chemistry; D013739:Testosterone / Q000737:chemistry; D014230:Triazoles / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004967:Estrogens; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D004970:Estrone; D000077384:Anastrozole; D013739:Testosterone