Abiraterone acetate/methylprednisolone, sold under the brand name Yonsa Mpred, is a composite package that contains both abiraterone acetate (Yonsa) and
methylprednisolone.[16] It was approved for medical use in Australia in March 2022.[16][17][18]
Experience with overdose of abiraterone acetate is limited.[2] There is no specific
antidote for abiraterone acetate overdose, and treatment should consist of general supportive measures, including monitoring of cardiac and liver function.[2]
Interactions
Abiraterone acetate is a
CYP3A4 substrate and hence should not be administered concurrently with strong
CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital.[20][19] It also inhibits
CYP1A2,
CYP2C9, and
CYP3A4 and likewise should not be taken concurrently with substrates of any of these enzymes that have a narrow therapeutic index.[20][19]
Spironolactone generally exerts anti-androgenic effects, but experimental evidence exists that it acts as an
androgen receptor agonist in an androgen-depleted environment, capable of inducing
prostate cancer proliferation.[21] This is supported by the observations described in several case reports.[22]
Pharmacology
Pharmacodynamics
Antiandrogenic activity
Abiraterone, the
active metabolite of abiraterone acetate, inhibits
CYP17A1, 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)[23][24] 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 of
dehydroepiandrosterone (DHEA) and
androstenedione, respectively, by its 17,20-lyase activity.[25] 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, and
dihydrotestosterone (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.[23][26] These concentrations are considerably lower than those achieved by castration alone (~20 ng/dL).[26] 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.[26] In accordance with its antiandrogenic action, abiraterone acetate decreases the weights of the
prostate gland,
seminal vesicles, and
testes.[27]
There has been interest in the use of abiraterone acetate for the treatment of
breast cancer due to its ability to lower
estrogen levels.[33] However, abiraterone has been found to act as a direct agonist of the
estrogen receptor, and induces proliferation of human breast cancer cells in vitro.[33] If abiraterone acetate is used in the treatment of breast cancer, it should be combined with an
estrogen receptor antagonist like
fulvestrant.[33] In spite of its antiandrogenic and estrogenic properties, abiraterone acetate does not appear to produce
gynecomastia as a side effect.[34]
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 highly
protein bound (>99%), and is metabolized in the liver by
CYP3A4 and
SULT2A1 to inactive metabolites. The drug is excreted in feces (~88%) and urine (~5%), and has a terminal half-life of 12 ± 5 hours.[19]
In the early 1990s, Mike Jarman, Elaine Barrie, and Gerry Potter of the
Cancer Research UK Centre for Cancer Therapeutics in the
Institute of Cancer Research in
London set out to develop drug treatments for prostate cancer. With the
nonsteroidal androgen synthesis inhibitor
ketoconazole as a model, they developed abiraterone acetate, filing a patent in 1993 and publishing the first paper describing it the following year.[10][39] Rights for commercialization of the drug were assigned to
BTG, a UK-based specialist healthcare company. BTG then licensed the product to Cougar Biotechnology, which began development of the commercial product.[40] In 2009, Cougar was acquired by
Johnson & Johnson, which
developed and sells the commercial product, and is conducting ongoing
clinical trials to expand its clinical uses.[41]
Abiraterone acetate was approved by the United States
Food and Drug Administration on 28 April 2011 for mCRPC.[42][43] The FDA press release made reference to a
phase 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.[44] Abiraterone acetate was also licensed by the
European Medicines Agency.[45] Until May 2012 the
National 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.[46] The use is currently limited to men who have already received one docetaxel-containing chemotherapy regimen.[47][48] It was subsequently approved for the treatment of mCSPC in 2018.[49]
Society and culture
Names
Abiraterone is the
INNTooltip International Nonproprietary Name and
BANTooltip British Approved Name of abiraterone acetate's major active metabolite abiraterone.[50][51]Abiraterone acetate is the
USANTooltip United States Adopted Name,
BANMTooltip British Approved Name Modified, and
JANTooltip Japanese Accepted Name of abiraterone acetate.[50] It is also known by its developmental code names CB-7630 and JNJ-212082, while CB-7598 was the developmental code name of abiraterone.[50][52]
Generic versions of abiraterone acetate have been approved in the United States.[53] Generic versions of Yonsa are not available as of November 2019[update].[54] In May 2019, the
United 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.[55]
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.[50]
Economics
A generic version is available in India at a price of $238 a month as of 2019[update].[58] 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.[58][59] A generic Zytiga version is available in India at a price of under $230 a month as of 2020.[60]
Research
Abiraterone acetate is under development for the treatment of
breast cancer and
ovarian cancer and as of March 2018, is in phase II clinical trials for these indications.[52] It was also under investigation for the treatment of
congenital adrenal hyperplasia, but no further development has been reported for this potential use.[52]
Prostate cancer
In people previously treated with docetaxel survival is increased by 3.9 months (14.8 months versus 10.9 months for placebo).[61]
In people with castration-refractory prostate cancer but who had not received chemotherapy those who received abiraterone acetate had a
progression-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.[62]
Abiraterone acetate may be useful for prevention of the
testosterone flare at the initiation of
GnRH agonist therapy in men with prostate cancer.[63]
^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.
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^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.
hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^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.
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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.
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^Alesini D, Iacovelli R, Palazzo A, Altavilla A, Risi E, Urbano F, Manai C, Passaro A, Magri V, Cortesi E (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.
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^de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI (May 2011).
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^Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE (January 2013).
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