title: Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.
abstract: We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.
authors.affiliation: CRC Department of Medical Oncology, University of Manchester, Christie Hospital, UK.
authors.forename: A
authors.initials: A
authors.lastname: Howell
authors.forename: D J
authors.initials: DJ
authors.lastname: DeFriend
authors.forename: J F
authors.initials: JF
authors.lastname: Robertson
authors.forename: R W
authors.initials: RW
authors.lastname: Blamey
authors.forename: L
authors.initials: L
authors.lastname: Anderson
authors.forename: E
authors.initials: E
authors.lastname: Anderson
authors.forename: F A
authors.initials: FA
authors.lastname: Sutcliffe
authors.forename: P
authors.initials: P
authors.lastname: Walton
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D000077267:Fulvestrant; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D012738:Sex Hormone-Binding Globulin; D000077267:Fulvestrant; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone