Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin.
OBJECTIVE
Toremifene (Fareston) is an orally administered triphenylethylene derivative with chemosensitizing activity in vitro in estrogen receptor-negative multidrug-resistant human breast cancer cells. The purpose of this study was to evaluate the effects of high-dose toremifene (600 mg/day for 5 days) on the plasma pharmacokinetics of doxorubicin in humans. The 600-mg dose had been previously established as the maximum tolerated dose in a phase I study of 35 patients.


METHODS
Doxorubicin was administered as an intravenous (i.v.) bolus over 15 min at a dose of 60 mg/m2 to 11 patients in the absence of toremifene pretreatment to establish baseline doxorubicin pharmacokinetics. Six of these patients received 600 mg/day toremifene for 5 days 4 weeks later, followed by an i.v. bolus dose of doxorubicin (60 mg/m2) on day 5. During toremifene pre-treatment, blood specimens (5 ml) were drawn at 0, 2, 4, and 24 h after dosing to assess peak levels. Following doxorubicin administration in each cycle, blood specimens were collected over a 72-h period for determination of the terminal half-life of elimination. Plasma concentrations of doxorubicin and toremifene were assessed by high-performance liquid chromatography (HPLC). Cumulative linear areas under the time-concentration curve (AUC) for doxorubicin were calculated using a noncompartmental model.


RESULTS
Prior to toremifene dosing, baseline doxorubicin pharmacokinetic studies showed an average terminal half-life of elimination of 40.04+/-7.86 h in 4 patients, and an average AUC of 135 600+/-67 600 microg/ml.h in 11 patients. In 4 of the patients receiving 600 mg/day toremifene for 5 days, the average terminal half-life of elimination was 38.12+/-7.81 h, and the average AUC was 141 900+/-62 900 microg/ml.h in 6 patients, i.e. a slight increase of 4.6%. No statistically significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed.


CONCLUSIONS
Toremifene does not appear to interfere with the elimination kinetics of doxorubicin.
Wurz
G T
GT
Department of Internal Medicine, Cancer Center, University of California, Davis, Sacramento 95817, USA.
Soc
L
L
Emshoff
V D
VD
Cadman
T B
TB
DeGregorio
M W
MW
D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D017312:Toremifene / Q000008:administration & dosage / Q000097:blood
D017312:Toremifene; D004317:Doxorubicin