Phase I study of the tolerance and pharmacokinetics of toremifene in patients with cancer.

Abstract

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.

• Authors: P C Kohler, J T Hamm, V J Wiebe, M W DeGregorio, I Shemano, D C Tormey
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 16 Suppl Pg. S19-26 (Aug 1990) ISSN: 0167-6806 [Print] Netherlands
• PMID: 2149280 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents
• Estrogen Antagonists
• Estrogens
• Gonadotropins
• Sex Hormone-Binding Globulin
• Tamoxifen
• Toremifene

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Climacteric (drug effects)
• Drug Administration Schedule
• Drug Evaluation
• Estrogen Antagonists (administration & dosage, adverse effects, pharmacokinetics)
• Estrogens (metabolism)
• Female
• Gonadotropins (blood)
• Humans
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism)
• Remission Induction
• Sex Hormone-Binding Globulin (metabolism)
• Tamoxifen (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Toremifene
• United States