Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Orion Corporation, Orionintie 1, FI-02200, Espoo, Finland
Pharmacotherapeutic group: Anti-estrogens
ATC code: L02BA02
Toremifene is a nonsteroidal triphenylethylene derivative. As other members of this class, e.g. tamoxifen and clomifene, toremifene binds to estrogen receptors and may produce estrogenic, anti-estrogenic or both effects, depending upon the duration of treatment, animal species, gender, target organ and variable selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and man and estrogenic in mice.
In post-menopausal breast cancer patients, toremifene treatment is associated with modest reductions in both total serum cholesterol and low density lipoprotein (LDL).
Toremifene binds specifically to estrogen receptors, competitively with oestradiol, and inhibits estrogeninduced stimulation of DNA synthesis and cell replication. In some experimental cancers and/or using high-dose, toremifene displays anti-tumour effects which are not estrogen-dependent.
The anti-tumour effect of toremifene in breast cancer is mainly due to the anti-estrogenic effect, although other mechanisms (changes in oncogene expression, growth factor secretion, induction of apoptosis and influence on cell cycle kinetics) may also be involved in the anti-tumour effect.
Toremifene is readily absorbed after oral administration. Peak concentrations in serum are obtained within 3 (range 2-5) hours. Food intake has no effect on the extent of absorption but may delay the peak concentrations by 1.5-2 hours. The changes due to food intake are not clinically significant.
The serum concentration curve can be described by a biexponential equation. The half-life of the first (distribution) phase is 4 (range 2-12) hours, and of the second (elimination) phase 5 (range 2-10) days. The basal disposition parameters (CL and V) could not be estimated due to the lack of intravenous study. Toremifene binds extensively (>99.5%) to serum proteins, mainly to albumin. Toremifene obeys linear serum kinetics at oral daily doses between 11 and 680 mg. The mean concentration of toremifene at steady-state is 0.9 (range 0.6-1.3) µg/ml at the recommended dose of 60 mg per day.
Toremifene is extensively metabolised. In human serum the main metabolite is N-demethyltoremifene with mean half-life of 11 (range 4-20) days. Its steady-state concentrations are about twice compared to those of the parent compound. It has similar anti-estrogenic, albeit weaker anti-tumour activity than the parent compound.
It is bound to plasma proteins even more extensively than toremifene, the protein bound fraction being >99.9%. Three minor metabolites have been detected in human serum: (deaminohydroxy)toremifene, 4-hydroxytoremifene, and N,N-didemethyltoremifene. Although they have theoretically interesting hormonal effects, their concentrations during toremifene treatment are too low to have any major biological importance.
Toremifene is eliminated mainly as metabolites to the faeces. Enterohepatic circulation can be expected. About 10% of the administered dose is eliminated via urine as metabolites. Owing to the slow elimination, steady-state concentrations in serum are reached in 4 to 6 weeks.
Clinical anti-tumour efficacy and serum concentrations have no positive correlation at the recommended daily dose of 60 mg.
No information is available concerning polymorphic metabolism. Enzyme complex, known to be responsible for the metabolism of toremifene in humans, is cytochrome P450-dependent hepatic mixed function oxidase. The main metabolic pathway, N-demethylation, is mediated mainly by CYP3A.
Pharmacokinetics of toremifene were investigated in an open study with four parallel groups of ten subjects: normal subjects, patients with impaired (mean AST 57 U/L – mean ALT 76 U/L – mean gamma GT 329 U/L) or activated liver function (mean AST 25 U/L – mean ALT 30 U/L – mean gamma GT 91 U/L – patients treated with antiepileptics) and patients with impaired renal function (creatinine: 176 µmol/L). In this study the kinetics of toremifene in patients with impaired renal function were not significantly altered as compared to normal subjects. The elimination of toremifene and its metabolites was significantly increased in patients with activated liver function and decreased in patients with impaired liver function.
The acute toxicity of toremifene is low with LD-50 in rats and mice of more than 2000 mg/kg. In repeated toxicity studies the cause of death in rats is gastric dilatation. In the acute and chronic toxicity studies most of the findings are related to the hormonal effects of toremifene. The other findings are not toxicologically significant. Toremifene has not shown any genotoxicity and has not been found to be carcinogenic in rats. In mice, estrogens induce ovarian and testicular tumours as well as hyperostosis and osteosarcomas. Toremifene has a species-specific estrogen-like effect in mice and causes similar tumours. These findings are postulated to be of little relevance for the safety in man, where toremifene acts mainly as an anti-estrogen.
Non clinical in vitro and in vivo studies have evidenced the potential of toremifene and its metabolite to prolong cardiac repolarisation and this can be attributed to the blockade of hERG channels.
In vivo, high plasma concentrations in monkeys caused a 24% prolongation in QTc, which is in line with QTc findings in humans.
It is also to be noted that the Cmax observed in the monkeys (1800 ng/ml) is two-fold compared to the mean Cmax observed in humans at a daily dose of 60 mg.
Action potential studies in isolated rabbit heart have shown that toremifene induce cardiac electrophysiological changes which start to develop at concentrations approximately 10 fold compared to the calculated free therapeutic plasma concentration in human.
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