Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine.

PURPOSE: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein alpha1-acid glycoprotein (AAG), which may limit tissue availability. In this phase I-II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. METHODS: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m2 i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. RESULTS: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 microM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 microM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. CONCLUSIONS: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo.

[Plasma concentrations of toremifene citrate and N-desmethyltoremifene in postmenopausal patients with breast cancer--comparison of 120 mg of toremifene citrate administered once a day and divided into 3 separate doses (t.i.d.)].

To determine whether plasma concentrations of toremifene citrate after administration of 120 mg/day of toremifene citrate given in three separate dose (t.i.d.) were similar to those when toremifene citrate was administered in a single daily doses (40 mg x 3 tablets), we examined changes in plasma concentrations of toremifene citrate (TOR) and its metabolite, N-desmethyltoremifene (TOR-1). In both the t.i.d. administration group and the single-dose administration group, plasma TOR and TOR-1 concentrations reached a constant state within 2 weeks after administration was started. Under the constant state, plasma TOR concentrations were 1,493.3 +/- 120.3 ng/ml in the t.i.d. administration group and 1,348 +/- 341.0 ng/ml in the single-dose administration group. Plasma TOR-1 concentrations were 2,378.3 +/- 186.5 ng/ml in the t.i.d. administration group and 2,144 +/- 475.3 ng/ml in the single-dose administration group. In both groups, plasma TOR-1 concentrations were 2 or more times higher than plasma TOR concentrations. These results show there were no differences in plasma concentrations between administration of 120 mg/day of toremifene citrate in divided daily doses (t.i.d.) and in a single daily dose. The two administration methods appear to produce clinically similar actions.

High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically.

PURPOSE: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. METHODS: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. RESULTS: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. CONCLUSIONS: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin.

PURPOSE: 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.

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin.

BACKGROUND: Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions. METHODS: The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration. RESULTS: Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase. CONCLUSIONS: Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.

Influence of age on toremifene pharmacokinetics.

Toremifene pharmacokinetics were compared in ten healthy young men (< 33 years) and elderly women (< 65 years). A single oral 120-mg dose of toremifene was given after an overnight fast and blood samples were collected over 28 days. Serum levels of the parent drug and the metabolites were determined; appropriate pharmacokinetic parameters were calculated and statistically evaluated. Toremifene peak concentrations (average 640 ng/ml) were achieved at 3.5 h. The area under the curve (AUC) and the apparent oral clearance were comparable in the young and elderly subjects. The half-life was prolonged (4.2 versus 7.2 days) and the apparent volume of distribution was increased (457 versus 627 1) in the elderly. The peak concentration of the main metabolite N-demethyltoremifene was lower (159 versus 233 ng/ml) and the half-life was prolonged (8.3 versus 19.1 days) in the elderly subjects, but the AUC values were comparable. The results suggest that toremifene is distributed more widely in the elderly but that its clearance is unaffected by age. It is concluded that the dosage requirement of the drug is unlikely to differ between young and elderly subjects.

High-dose toremifene in advanced renal-cell carcinoma.

Toremifene (Fareston)-a novel antiestrogenic drug with a triphenylethylene structure-is effective in the treatment of postmenopausal breast cancer patients. It can be safely given even at high doses of up to 300 mg/day. The purpose of the present study was to investigate the effect and tolerability of high-dose toremifene in the treatment of patients with advanced renal-cell carcinoma (RCC). A total of 36 patients started treatment with toremifene at 300 mg/day, including 26 men and 10 women. Their mean age was 56 years (range 35-75 years). In all, 19 patients were nephrectomized. One patient was not evaluable for response because of insufficient treatment time. The response rate was 17%, including one complete response (CR, 3%) lasting for 121+ weeks and five partial responses (PRs, 14%) with a mean duration of 40+ weeks. Ten cases of no change (NC, 28%) had a mean duration of 24 weeks. There was no significant difference in the response rate when patients with lung metastases alone were compared with patients showing metastases of other sites with or without lung metastases. Total pain control was achieved in 45% of the patients who had pain at the beginning of the treatment, and partial control was attained in 20%. Ten patients (28%) developed adverse reactions, which led to discontinuation of the treatment in one case. Blood samples were taken from 16 patients on days 0, 1, 3, 7, 14, and 28 for drug analyses. The concentration of toremifene and its main metabolites measured in serum were about 1.5 times that detected after a conventional dose of 60 mg/day. It can be concluded that high-dose toremifene is an effective and safe palliative treatment in advanced RCC.

Targeting chemosensitizing doses of toremifene based on protein binding.

Toremifene is currently being evaluated as a chemosensitizing agent in doxorubicin-resistant patients. Although concentrations of > 2 microM reverse resistance in vitro, target concentrations required to reverse multidrug resistance (MDR) in vivo may be highly influenced by variables such as protein binding in serum. We examined the effects of high serum concentrations on the cellular accumulation of toremifene in an MDR MDA-MB-A-1 human breast-cancer cell line. We then examined the cellular accumulation of doxorubicin at various toremifene concentrations in 5% - 100% serum. We also measured the concentrations of toremifene and its major metabolites in plasma specimens obtained from two patients receiving 360 mg/day for 5 days in a phase I study. Our results show that (1) high serum concentrations decrease toremifene accumulation, (2) toremifene concentrations of < or = 2.5 microM enhance doxorubicin accumulation, and (3) patients achieve plasma toremifene concentrations of 10-15 microM following doses of 360 mg/day x 5 days. Our findings suggest that in vivo toremifene concentrations well above those used to reverse resistance in vitro are required to overcome the effect of high serum-protein binding.