Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer

Abstract

A multicenter phase I pharmacokinetic study of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites. N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1-2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.

Mass spectrometric characterization of urinary toremifene metabolites for doping control analyses

“…In the case of toremifene, pharmacokinetic and pharmacodynamic studies with detection of toremifene and its metabolites in plasma and faeces, have been reported [13][14][15][16][17][18][19][20][21][22][23][24][25]. Few analytical methods for the urinary detection of toremifene administration have been developed [3,14,[26][27][28][29].…”

A bioassay for antiestrogenic activity — potential utility in drug development and monitoring effectivein vivo dosing

“…Fabian et al examined tamoxifen plasma kinetics after continuous oral dosing and found that most patients achieved steady-state levels within 16 weeks of therapy, although a wide range of concentrations were reported [5]. Similar pharmacokinetic results were reported for toremifene following 8 weeks of therapy [3]. Both studies show a wide variation in steady-state concentrations.…”

“…However, they are generally considered to be antiestrogens in human breast tumors due to their inhibitory effects on estrogen-stimulated cell growth. The major metabolic pathways for toremifene and tamoxifen include N-desmethylation and 4-hy-droxylation [2,3].…”

Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis

“…An in vivo study in dimethylbenz(a)anthracene (DMBA)-induced breast tumor mice using 11 C-labeled toremifene revealed that this drug, when orally administered, is not selectively distributed but diffuses into most tissues including the liver, spleen, brain and heart [46]. In healthy volunteers, based on apparent oral clearance, the apparent volume of distribution ranged from 457 to 958 l [42,43,47,48].…”