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.
Theaffinity 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 ofestradiol 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 theERα and 15.4 ± 3.1 nM for theERβ.[20] In other rat ER studies, toremifene had 3–9% of the affinity of estradiol for the ER while itsmetabolitesN-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 antiestrogenicpotency than toremifenein vitro in one study,[29] but not in another.[28] 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenicin 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 aprodrug.[31]
Toremifene is very similar totamoxifen 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 ahepatocarcinogen in animals and may have less potential forgenotoxicity.[6][3] However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms ofeffectiveness,tolerability, andsafety, and hence the clinical use of toremifene has been somewhat limited.[6][3] Toremifene is thought to have about one-third of thepotency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.[32]
Thebioavailability 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 atsteady state with a dosage of 60 mg/day are 800 to 879 ng/mL.[1] Levels ofN-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 ismetabolized in theliver primarily byCYP3A4 and then undergoes secondaryhydroxylation.[2] Themetabolites of toremifene includeN-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]
Theelimination half-life of toremifene is 3 to 7 days in healthy individuals.[1] In people withimpaired liver function, the half-life is 11 days.[1] The elimination half-lives of the metabolites of toremifene are 5 to 21 days forN-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 toenterohepatic recirculation and high plasma protein binding.[1][5] Toremifene iseliminated 70% in thefeces, as metabolites.[2]
Toremifene was introduced in theUnited States in 1997.[11][12] It was the firstantiestrogen to be introduced in this country since tamoxifen in 1978.[13]
Toremifene is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, whiletoremifene citrate is itsUSANTooltip United States Adopted Name andJANTooltip Japanese Accepted Name andtorémifène is itsDCFTooltip Dénomination Commune Française.[42][43][44][45]
Toremifene was also evaluated for prevention ofprostate cancer and had the tentative brand name Acapodene.[46]
In 2007 the pharmaceutical companyGTx, Inc was conducting two different phase 3clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects ofandrogen deprivation therapy (ADT) (especially vertebral/spine fractures andhot flashes, lipid profile, andgynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high gradeprostatic 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 ofbicalutamide-induced gynecomastia.[15]
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 inGleason 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 toremifeneJ 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
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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.
