Cancer Chemother Pharmacol (1990) 25: 247- 251 ancer hemotherapy and harmacology 9 Springer-Verlag 1990 Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer* Valerie J. Wiebe l, Christopher C. Benz 2, Irving Shemano 3, Timothy B. Cadman 1, and Michael W. DeGregorio l 1 Section of Medical Oncology, Department of Internal Medicine, Yale University, 2 Cancer Research Institute, University of California, San Francisco, CA, and 3 Adria Laboratories, Columbus, Ohio, USA Summary. A multicenter phase I pharmacokineticstudy of a new triphenylethylene antiestrogen, toremifene, was ex- amined 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-desmethyl- toremifene 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 rag. 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. Introduction Antiestrogen therapy is a form of hormonal therapy that has been used in the treatment of breast cancer since 1974. In recent years, numerous clinical studies have combined antiestrogen therapy with chemotherapy in an attempt to improve response rates in advanced breast cancer. Cur- rently, the most commonly used antiestrogenic agent for the treatment of patients with advanced breast cancer is tamoxifen. Although many patients with estrogen-recep- tor-positive tumors may benefit from tamoxifen therapy, there remains a patient population that fails to respond to antiestrogen therapy. Toremifene is a new triphenylethylene antiestrogen compound that is structurally similar to tamoxifen (Fig. 1). The efficacy of toremifene and tamoxifen in patients with estrogen-receptor-positive breast cancer appears to be * This work was supported by a grant from Adria Laboratories Offprint requests to: Michael W. DeGregorio, Section of Medical Oncology, Yale University, 333 Cedar Street, P. O. Box 3333, New Haven, CT 06510, USA comparable, but effective daily doses of toremifene are higher (60 mg/day) than those of tamoxifen (20 rag/day) [7]. Following oral administration, toremifene undergoes metabolic conversion by both the N-desmethylation and 4- hydroxylation pathways. The two major active metabo- lites, N-desmethyltoremifene and 4-hydroxytoremifene are detected in plasma soon after the start of therapy. In the present phase I study, the steady-state pharmacokinetics of toremifene and its major metabolites were examined fol- lowing oral administration of the drug. Patients and methods Patient characteristics. A total of 70 patients with advanced breast cancer were entered for evaluation of the phar- macokinetics of toremifene. Postmenopausal patients refractory to previous cytotoxic, hormonal, and radiation therapy were eligible. Patients with prior hysterectomies, oophorectomies, or salpingoophorectomies were included. Eligibility was independent of estrogen receptor status. Patients receiving prior therapies were eligible in the ab- sence of myelosuppression (WBC >3,500; granulocytes, > 1,500; platelets, >_ 100,000). A washout period of at least 3 weeks was required following previous therapy. Patients were required at study entry to have an ECOG perfor- mance status of 0-2. Adequate renal function, defined as a serum creatinine level of <2.0 mg/dl and a 24-h creatinine clearance of >50 ml/min, were required. Patients were required to have serum bilirubin levels of <2.0 mg/dl as well as SGOT and SGPT values < 1.5 times the upper limit of normal at each institute. Toremifene admin&tration. Patients were randomly as- signed to one of six (10, 20, 40, 60, 200, or 400 mg/day) treatment groups. Each patient received single daily doses of toremifene by oral administration. Doses were given as 10-, 20-, 60-, and 200-rag tablets each morning, 30 min prior to breakfast. Treatment was continued for 8 weeks to enable the attainment of steady-state blood levels of toremifene and its major metabolites. On days requiring blood samples, patients were instructed to delay tablet in- gestion until after blood was drawn. Patient compliance was documented by weekly tablet counts. Blood sampling and drug assay. Blood samples were col- lected in pre-iced heparinized tubes at various time points during and after the cessation of toremifene therapy. The