Abiraterone acetate/methylprednisolone, sold under the brand name Yonsa Mpred, is a composite package that contains both abiraterone acetate (Yonsa) andmethylprednisolone.[15] It was approved for medical use in Australia in March 2022.[15][16][17]
Experience with overdose of abiraterone acetate is limited.[2] There is no specificantidote for abiraterone acetate overdose, and treatment should consist of general supportive measures, including monitoring of cardiac and liver function.[2]
Abiraterone acetate is aCYP3A4 substrate and hence should not be administered concurrently with strongCYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital.[19][18] It also inhibitsCYP1A2,CYP2C9, andCYP3A4 and likewise should not be taken concurrently with substrates of any of these enzymes that have a narrow therapeutic index.[19][18]
Spironolactone generally exerts anti-androgenic effects, but experimental evidence exists that it acts as anandrogen receptor agonist in an androgen-depleted environment, capable of inducingprostate cancer proliferation.[20] This is supported by the observations described in several case reports.[21]
Abiraterone, theactive metabolite of abiraterone acetate.Steroidogenesis, showing the actions of 17α-hydroxylase and 17,20-lyase in green boxes at left.
Abiraterone, theactive metabolite of abiraterone acetate, inhibitsCYP17A1, which manifests as two enzymes, 17α-hydroxylase (IC50Tooltip half-maximal inhibitory concentration = 2.5 nM) and 17,20-lyase (IC50 = 15 nM) (approximately 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase)[22][23] that are expressed in testicular, adrenal, and prostatic tumor tissues. CYP17A1 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation ofdehydroepiandrosterone (DHEA) andandrostenedione, respectively, by its 17,20-lyase activity.[24] DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17A1 activity by abiraterone acetate thus decreases circulating levels of androgens such as DHEA,testosterone, anddihydrotestosterone (DHT). Abiraterone acetate, via abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable) when added to castration.[22][25] These concentrations are considerably lower than those achieved by castration alone (~20 ng/dL).[25] The addition of abiraterone acetate to castration was found to reduce levels of DHT by 85%, DHEA by 97 to 98%, and androstenedione by 77 to 78% relative to castration alone.[25] In accordance with its antiandrogenic action, abiraterone acetate decreases the weights of theprostate gland,seminal vesicles, andtestes.[26]
There has been interest in the use of abiraterone acetate for the treatment ofbreast cancer due to its ability to lowerestrogen levels.[32] However, abiraterone has been found to act as a direct agonist of theestrogen receptor, and induces proliferation of human breast cancer cellsin vitro.[32] If abiraterone acetate is used in the treatment of breast cancer, it should be combined with anestrogen receptor antagonist likefulvestrant.[32] In spite of its antiandrogenic and estrogenic properties, abiraterone acetate does not appear to producegynecomastia as a side effect.[33]
After oral administration, abiraterone acetate, the prodrug form in the commercial preparation, is converted into the active form, abiraterone. This conversion is likely to be esterase-mediated and not CYP-mediated. Administration with food increases absorption of the drug and thus has the potential to result in increased and highly variable exposures; the drug should be consumed on an empty stomach at least one hour before or two hours after food. The drug is highlyprotein bound (>99%), and is metabolized in the liver byCYP3A4 andSULT2A1 to inactive metabolites. The drug is excreted in feces (~88%) and urine (~5%), and has a terminal half-life of 12 ± 5 hours.[18]
In the early 1990s, Mike Jarman, Elaine Barrie, and Gerry Potter of theCancer Research UK Centre for Cancer Therapeutics in theInstitute of Cancer Research inLondon set out to develop drug treatments for prostate cancer. With thenonsteroidal androgen synthesis inhibitorketoconazole as a model, they developed abiraterone acetate, filing a patent in 1993 and publishing the first paper describing it the following year.[11][38] Rights for commercialization of the drug were assigned toBTG, a UK-based specialist healthcare company. BTG then licensed the product to Cougar Biotechnology, which began development of the commercial product.[39] In 2009, Cougar was acquired byJohnson & Johnson, whichdeveloped and sells the commercial product, and is conducting ongoingclinical trials to expand its clinical uses.[40]
Abiraterone acetate was approved by the United StatesFood and Drug Administration on 28 April 2011 for mCRPC.[41][42] The FDA press release made reference to aphase IIIclinical trial in which abiraterone acetate use was associated with a median survival of 14.8 months versus 10.9 months with placebo; the study was stopped early because of the successful outcome.[43] Abiraterone acetate was also licensed by theEuropean Medicines Agency.[44] Until May 2012 theNational Institute for Health and Clinical Excellence (NICE) did not recommend use of the drug within the NHS on cost-effectiveness grounds. This position was reversed when the manufacturer submitted revised costs.[45] The use is currently limited to men who have already received one docetaxel-containing chemotherapy regimen.[46][47] It was subsequently approved for the treatment of mCSPC in 2018.[48]
Abiraterone is theINNTooltip International Nonproprietary Name andBANTooltip British Approved Name of abiraterone acetate's major active metabolite abiraterone.[49][50]Abiraterone acetate is theUSANTooltip United States Adopted Name,BANMTooltip British Approved Name Modified, andJANTooltip Japanese Accepted Name of abiraterone acetate.[49] It is also known by its developmental code namesCB-7630 andJNJ-212082, whileCB-7598 was the developmental code name of abiraterone.[49][51]
Generic versions of abiraterone acetate have been approved in the United States.[52] Generic versions of Yonsa are not available as of November 2019[update].[53] In May 2019, theUnited States Court of Appeals for the Federal Circuit upheld a Patent Trial and Appeal Board decision invalidating a patent by Johnson & Johnson on abiraterone acetate.[54]
Abiraterone acetate is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere in Europe, Australia, New Zealand, Latin America, Asia, and Israel.[49]
A generic version is available in India at a price of $238 a month as of 2019[update].[57] The National Centre for Pharmacoeconomics initially found abiraterone acetate to not be cost effective based on prices in 2012, however following an agreement to supply at a lower price it was accepted in 2014.[57][58] A generic Zytiga version is available in India at a price of under $230 a month as of 2020.[59]
Abiraterone acetate is under development for the treatment ofbreast cancer andovarian cancer and as of March 2018, is in phase II clinical trials for these indications.[51] It was also under investigation for the treatment ofcongenital adrenal hyperplasia, but no further development has been reported for this potential use.[51]
In people previously treated with docetaxel survival is increased by 3.9 months (14.8 months versus 10.9 months for placebo).[60]
In people with castration-refractory prostate cancer but who had not received chemotherapy those who received abiraterone acetate had aprogression-free survival of 16.5 months rather than 8.3 months with placebo. After a median follow-up period of 22.2 months, overall survival was better with abiraterone acetate.[61]
Abiraterone acetate may be useful for prevention of thetestosterone flare at the initiation ofGnRH agonist therapy in men with prostate cancer.[62]
^Potter GA, Barrie SE, Jarman M, Rowlands MG (June 1995). "Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer".Journal of Medicinal Chemistry.38 (13):2463–2471.doi:10.1021/jm00013a022.PMID7608911.
^abScowcroft H (21 September 2011)."Where did abiraterone come from?".Journal of Medicinal Chemistry.38 (13). Cancer Research UK:2463–2471.Archived from the original on 25 September 2011. Retrieved28 September 2011.
^World Health Organization (2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Luthy IA, Begin DJ, Labrie F (November 1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture".Journal of Steroid Biochemistry.31 (5):845–52.doi:10.1016/0022-4731(88)90295-6.PMID2462135.
^Attard G, Belldegrun AS, de Bono JS (December 2005). "Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer".BJU International.96 (9):1241–6.doi:10.1111/j.1464-410X.2005.05821.x.PMID16287438.S2CID36575315.
^abcCapper CP, Larios JM, Sikora MJ, Johnson MD, Rae JM (May 2016). "The CYP17A1 inhibitor abiraterone exhibits estrogen receptor agonist activity in breast cancer".Breast Cancer Research and Treatment.157 (1):23–30.doi:10.1007/s10549-016-3774-3.PMID27083183.S2CID9912289.
^Alesini D, Iacovelli R, Palazzo A, Altavilla A, Risi E, Urbano F, et al. (2013). "Multimodality treatment of gynecomastia in patients receiving antiandrogen therapy for prostate cancer in the era of abiraterone acetate and new antiandrogen molecules".Oncology.84 (2):92–9.doi:10.1159/000343821.PMID23128186.S2CID207547652.
^"FDA Approval for Abiraterone Acetate". U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Archived fromthe original on 28 July 2011. Retrieved4 September 2011.
