Clinical data | |
---|---|
Pronunciation | /ˈtɔːrəmɪfiːn/ |
Trade names | Fareston, others |
Other names | (Z)-Toremifene; 4-Chlorotamoxifen; 4-CT; Acapodene; CCRIS-8745; FC-1157; FC-1157a; GTx-006; NK-622; NSC-613680 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a608003 |
License data | |
Routes of administration | By mouth |
Drug class | Selective estrogen receptor modulator |
ATC code | |
Pharmacokinetic data | |
Bioavailability | Good/~100% [1] [2] |
Protein binding | 99.7% [1] |
Metabolism | Liver (CYP3A4) [3] [2] |
Metabolites | N-Desmethyltoremifene; 4-Hydroxytoremifene; Ospemifene [4] [5] |
Elimination half-life | Toremifene: 3–7 days [1] Metabolites: 4–21 days [2] [5] [1] |
Excretion | Feces: 70% (as metabolites) [2] |
Identifiers | |
| |
CAS Number |
|
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.125.139 |
Chemical and physical data | |
Formula | C26H28ClNO |
Molar mass | 405.97 g·mol−1 |
3D model (JSmol) | |
| |
| |
(verify) |
Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. [5] [6] [4] It is taken by mouth. [5]
Side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. [3] [7] It can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer. [3] High blood calcium levels can occur in women with bone metastases. [3]
The medication is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol. [3] [7] It has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts. [6] [8] [9] [3] It is a triphenylethylene derivative and is closely related to tamoxifen. [10]
Toremifene was introduced for medical use in 1997. [11] [12] It was the first antiestrogen to be introduced since tamoxifen in 1978. [13] It is available as a generic medication in the United States. [14]
Toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors. [5] [6] This is its only approved use in the United States. [5] It shows equivalent effectiveness to tamoxifen for this indication. [6] [15] Toremifene has been found to be effective in the treatment of breast pain and may be a more effective medication than tamoxifen for this indication. [16] It also has superior effects on bone mineral density and lipid profile, including levels of cholesterol and triglycerides, compared to tamoxifen. [15] Toremifene has been reported to significantly improve symptoms of gynecomastia in men. [17]
Toremifene is provided in the form of 60 mg oral tablets. [18] [19]
The side effects of toremifene are similar to those of tamoxifen. [3] The most common side effect is hot flashes. [3] Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. [3] [7] In women with bone metastases, hypercalcemia may occur. [3] Toremifene has a small risk of thromboembolic events. [3] Cataracts, vision changes, and elevation of liver enzymes have been reported. [3] [7] The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias. [3] The risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing QT prolongation, and in those taking other QT-prolonging drugs. [3] Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer. [3]
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]
Toremifene is a substrate of CYP3A4, a cytochrome P450 enzyme, and hence drugs that induce or inhibit this enzyme can respectively decrease or increase levels of toremifene in the body. [3]
Toremifene is a selective estrogen receptor modulator (SERM). [3] [7] [20] That is, it is a selective mixed agonist–antagonist of the estrogen receptors (ERs), with estrogenic actions in some tissues and antiestrogenic actions in other tissues. [3] [7] The medication has estrogenic effects in bone, partial estrogenic effects in the uterus and liver, and antiestrogenic effects in the breasts. [6] [8] [9] [3]
Medication | Breast | Bone | Liver | Uterus | Vagina | Brain | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Lipids | Coagulation | SHBG Tooltip Sex hormone-binding globulin | IGF-1 Tooltip Insulin-like growth factor 1 | Hot flashes | Gonadotropins | |||||||||
Estradiol | + | + | + | + | + | + | + | + | + | + | ||||
"Ideal SERM" | – | + | + | ± | ± | ± | – | + | + | ± | ||||
Bazedoxifene | – | + | + | + | + | ? | – | ± | – | ? | ||||
Clomifene | – | + | + | ? | + | + | – | ? | – | ± | ||||
Lasofoxifene | – | + | + | + | ? | ? | ± | ± | – | ? | ||||
Ospemifene | – | + | + | + | + | + | ± | ± | – | ± | ||||
Raloxifene | – | + | + | + | + | + | ± | – | – | ± | ||||
Tamoxifen | – | + | + | + | + | + | + | – | – | ± | ||||
Toremifene | – | + | + | + | + | + | + | – | – | ± | ||||
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 metabolites N-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] [3] 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] [4] 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] [4] 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]
Toremifene has been found to have antigonadotropic effects in postmenopausal women, [33] progonadotropic effects in men, [34] to increase sex hormone-binding globulin levels, [33] and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men. [35]
In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the estrogen-related receptor γ (ERRγ). [36]
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 99.7% bound to plasma proteins, with 92% bound specifically to albumin, about 6% to β1 globulin fraction, and about 2% to a fraction between albumin and α1 globulins. [37] [1] The apparent volume of distribution of toremifene ranged from 457 to 958 L. [37]
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] [5]
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] [5] The long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding. [1] [3] Toremifene is eliminated 70% in the feces, as metabolites. [2]
Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen. [10] It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene). [40] [41]
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]
Toremifene is the generic name of the drug and its INN Tooltip International Nonproprietary Name and BAN Tooltip British Approved Name, while toremifene citrate is its USAN Tooltip United States Adopted Name and JAN Tooltip Japanese Accepted Name and torémifène is its DCF Tooltip Dénomination Commune Française. [42] [43] [44] [45]
Toremifene is marketed almost exclusively under the brand name Fareston. [43] [45]
Toremifene is marketed widely throughout the world and is available in the United States, the United Kingdom, Ireland, many other European countries, South Africa, Australia, New Zealand, and elsewhere throughout the world. [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]
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]
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.
Anastrozole, sold under the brand name Arimidex among others, is a medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.
Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course of treatment that usually lasts for five days.
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.
Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.
Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken multiple times a day by mouth or by injection into a vein.
Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. It is taken by mouth.
Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.
Arzoxifene is a selective estrogen receptor modulator (SERM) of the benzothiophene group which was never marketed. It is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.
Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.
Nafoxidine or nafoxidine hydrochloride is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.
Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.
Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.
D-15414 is a nonsteroidal weak estrogen of the 2-phenylindole group which was never marketed. It is the major metabolite of the selective estrogen receptor modulator (SERM) zindoxifene (D-16726). D-15414 has high affinity for the estrogen receptor (ER) and inhibits the growth of ER-positive MCF-7 breast cancer cells in vitro. However, contradictorily, subsequent research found that the drug produced fully estrogenic effects in vitro similarly to but less actively than estradiol, with no antiestrogenic activity observed. The reason for the discrepancy between the findings is unclear, though may be due to methodology. The unexpected estrogenic activity of D-15414 may be responsible for the failure of zindoxifene in clinical trials as a treatment for breast cancer.
High-dose estrogen therapy (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of these hormones that occur during pregnancy. HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others. Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used.
The pharmacology of bicalutamide, a nonsteroidal antiandrogen (NSAA), has been well-characterized. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.
The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.