Toremifene appears to be safer than tamoxifen.[15] It has a lower risk of venous thromboembolism (VTE) (e.g., pulmonary embolism), stroke, and cataracts.[15] The lower risk of VTE may be related to the fact tamoxifen decreases levels of the antithrombin III to a significantly greater extent than either 60 or 200 mg/day toremifene.[15]
Effect:+ = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.
The affinity of toremifene for the ER is similar to that of tamoxifen.[6][21][22] In studies using rat ER, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the ER.[23][24][25][26][27][22] The affinities (Ki) of toremifene at the human ERs have been reported as 20.3 ± 0.1 nM for the ERα and 15.4 ± 3.1 nM for the ERβ.[20] In other rat ER studies, toremifene had 3–9% of the affinity of estradiol for the ER while its metabolitesN-desmethyltoremifene and 4-hydroxytoremifene had 3–5% and 64–158% of the affinity of estradiol for the ER, respectively.[28][29][30] The affinity of another metabolite, 4-hydroxy-N-desmethyltoremifene, was not assessed.[29] 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic potency than toremifene in vitro in one study,[29] but not in another.[28] 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenic in vitro.[28] The metabolites of toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication.[1][29][28] On the other hand, some authorities consider toremifene not to be a prodrug.[31]
Toremifene is very similar to tamoxifen and shares most of its properties.[6][8][9][5] There are some indications that toremifene may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity.[6][3] However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited.[6][3] Toremifene is thought to have about one-third of the potency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.[32]
The bioavailability of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%.[1][2] Levels of toremifene at steady state with a dosage of 60 mg/day are 800 to 879 ng/mL.[1] Levels of N-desmethyltoremifene at steady state with toremifene were 3,058 ng/mL at 60 mg/day, 5,942 ng/mL at 200 mg/day, and 11,913 ng/mL at 400 mg/day.[1] Levels of 4-hydroxytoremifene at steady state with toremifene were 438 ng/mL at 200 mg/day and 889 ng/mL at 400 mg/day.[1] Concentrations of toremifene increase linearly across a dose range of 10 to 680 mg.[37][38]
Toremifene is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation.[2] The metabolites of toremifene include N-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-N-desmethyltoremifene, among others.[1][29][2][39]Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene.[1][4]
Elimination
The elimination half-life of toremifene is 3 to 7 days in healthy individuals.[1] In people with impaired liver function, the half-life is 11 days.[1] The elimination half-lives of the metabolites of toremifene are 5 to 21 days for N-desmethyltoremifene, 5 days for 4-hydroxytoremifene, and 4 days for ospemifene.[1][2][4] The long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding.[1][5] Toremifene is eliminated 70% in the feces, as metabolites.[2]
Toremifene was introduced in the United States in 1997.[11][12] It was the first antiestrogen to be introduced in this country since tamoxifen in 1978.[13]
Society and culture
Generic names
Toremifene is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while toremifene citrate is its USANTooltip United States Adopted Name and JANTooltip Japanese Accepted Name and torémifène is its DCFTooltip Dénomination Commune Française.[42][43][44][45]
Brand names
Toremifene is marketed almost exclusively under the brand name Fareston.[43][45]
Toremifene was also evaluated for prevention of prostate cancer and had the tentative brand name Acapodene.[46]
In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008[47]
An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,[48] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.[49]
Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.[50]
Toremifene may be useful in the prevention of bicalutamide-induced gynecomastia.[15]
Phase III Trial Results
A double-blind, placebo-controlled, randomized, 3 year clinical trial of toremifene was conducted using a sample of 1,260 men. Subjects had a median age of 64 years and were diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN), which is considered premalignant, though Thompson and Leach feel a low grade PIN could also be deemed premalignant.[51]
The sponsor, GTx, who designed and managed the study, found 34.7% of the placebo and 32.3% of the toremifene groups had cancer events. No distinction was found in Gleason scores of either group.[52]
Previous murine studies using transgenic adenocarcinoma of mouse prostate (TRAMP) mice showed toremifene prevented palpable tumors in 60% of the animals. This study used toremifene as an early prophylactic, which differentiates it from the phase III human studies.[53]
^ abTaneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA (March 2006). "Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy". Expert Opin Investig Drugs. 15 (3): 293–305. doi:10.1517/13543784.15.3.293. PMID16503765. S2CID29510508.
^ abKallio S, Kangas L, Blanco G, Johansson R, Karjalainen A, Perilä M, Pippo I, Sundquist H, Södervall M, Toivola R (1986). "A new triphenylethylene compound, Fc-1157a. I. Hormonal effects". Cancer Chemother Pharmacol. 17 (2): 103–8. doi:10.1007/BF00306736. PMID2941176. S2CID13238715.
^Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM (March 2001). "Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens". Chem Res Toxicol. 14 (3): 280–94. doi:10.1021/tx000208y. PMID11258977.
^Chander SK, Sahota SS, Evans TR, Luqmani YA (December 1993). "The biological evaluation of novel antioestrogens for the treatment of breast cancer". Crit Rev Oncol Hematol. 15 (3): 243–69. doi:10.1016/1040-8428(93)90044-5. PMID8142059.
^ abcdeRobinson SP, Parker CJ, Jordan VC (August 1990). "Preclinical studies with toremifene as an antitumor agent". Breast Cancer Res Treat. 16 (Suppl): S9–17. doi:10.1007/BF01807139. PMID2149286. S2CID19989845.
^Ariazi EA, Jordan VC (2006). "Estrogen-related receptors as emerging targets in cancer and metabolic disorders". Curr Top Med Chem. 6 (3): 203–15. doi:10.2174/1568026610606030203. PMID16515477.
^ abcGennari L, Merlotti D, Stolakis K, Nuti R (April 2012). "Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis". Expert Opin Drug Metab Toxicol. 8 (4): 505–13. doi:10.1517/17425255.2012.665873. PMID22356442. S2CID19547631.
^Price N, Sartor O, Hutson T, Mariani S (2005). "Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer". Clin Prostate Cancer. 3 (4): 211–4. doi:10.1016/s1540-0352(11)70089-0. PMID15882476.
^Taneja, S. S., Morton, R., Barnette, G., Sieber, P., Hancock, M. L., and Steiner, M., Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene J Clin Oncol, 2013;31:523-9. https://ascopubs.org/doi/abs/10.1200/JCO.2012.41.7634=[permanent dead link] Retrieved 31 July 2019
^Raghow, S., Hooshdaran, M. Z., Katiyar, S., and Steiner, M. S., Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. Cancer Research 2002;62:1370-6. http://cancerres.aacrjournals.org/content/62/5/1370= Retrieved 31 July 2019
Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA (2006). "Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy". Expert Opin Investig Drugs. 15 (3): 293–305. doi:10.1517/13543784.15.3.293. PMID16503765. S2CID29510508.
Zhou WB, Ding Q, Chen L, Liu XA, Wang S (2011). "Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials". Breast Cancer Res. Treat. 128 (3): 625–31. doi:10.1007/s10549-011-1556-5. PMID21553116. S2CID36985808.
Gennari L, Merlotti D, Stolakis K, Nuti R (2012). "Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis". Expert Opin Drug Metab Toxicol. 8 (4): 505–13. doi:10.1517/17425255.2012.665873. PMID22356442. S2CID19547631.
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