Abiraterone acetate

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Abiraterone acetate
Abiraterone.svg
Abiraterone-3D-balls.png
Systematic (IUPAC) name
(3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol
Clinical data
Trade names Zytiga
AHFS/Drugs.com monograph
MedlinePlus a611046
Licence data US FDA:link
Pregnancy
category
  • AU: D
  • US: X (Contraindicated)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Protein binding >99%
Metabolism CYP3A4- and SULT2A1-mediated
Biological half-life 12 ± 5 hours
Excretion Faecal (88%), renal (5%)
Identifiers
CAS Number 154229-19-3 N
ATC code L02BX03 (WHO)
PubChem CID: 132971
IUPHAR/BPS 6745
ChemSpider 117349 YesY
UNII G819A456D0 YesY
ChEMBL CHEMBL254328 YesY
Chemical data
Formula C24H31NO
Molecular mass 349.509 g/mol
  • O[C@@H]2C/C1=C/C[C@@H]4[C@@H]([C@@]1(C)CC2)CC[C@@]3(C(=C/C[C@H]34)\c5cccnc5)C
  • InChI=1S/C24H31NO/c1-23-11-9-18(26)14-17(23)5-6-19-21-8-7-20(16-4-3-13-25-15-16)24(21,2)12-10-22(19)23/h3-5,7,13,15,18-19,21-22,26H,6,8-12,14H2,1-2H3/t18-,19-,21-,22-,23-,24+/m0/s1 YesY
  • Key:GZOSMCIZMLWJML-VJLLXTKPSA-N YesY
 NYesY (what is this?)  (verify)

Abiraterone acetate (INN, USAN, BAN, JAN) (brand names Zytiga, Abiratas, Abretone, Abirapro) is a steroidal antiandrogen, specifically an androgen synthesis inhibitor, used in combination with prednisone in metastatic castration-resistant prostate cancer (previously called hormone-resistant or hormone-refractory prostate cancer) – i.e., prostate cancer not responding to androgen deprivation or treatment with androgen receptor antagonists. It is a prodrug to the active agent abiraterone, and is marketed by Janssen Biotech under the trade name Zytiga. In addition, Intas Pharmaceuticals markets the drug under the trade name Abiratas, Cadila Pharmaceuticals markets the drug as Abretone, and Glenmark Pharmaceuticals as Abirapro.

Abiraterone acetate was approved by the United States Food and Drug Administration on April 28, 2011.[1][2] The FDA press release made reference to a phase III clinical trial in which abiraterone 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.[3]

Medical uses

Abiraterone acetate is indicated for use in combination with prednisone as a treatment for metastatic castration-resistant prostate cancer.[4][5][6][7] It has received FDA (28 April 2011), EMA (23 September 2011), MHRA (5 September 2011) and TGA (1 March 2012) approval for this indication.[4][5][6][7] In Australia it is covered by the Pharmaceutical Benefits Scheme when being used to treat castration-resistant prostate cancer and given in combination with prednisone/prednisolone (subject to the conditions that the patient is not currently receiving chemotherapy, is either resistant or intolerant of docetaxel, has a WHO performance status of <2, and his disease has not since become progressive since treatment with PBS-subsidised abiraterone acetate has commenced).[8]

Adverse effects

Adverse effects by frequency:[4][5][6][7][9]
Very common (>10% frequency):

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Common (1-10% frequency):

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Uncommon (0.1-1% frequency):

Rare (<0.1% frequency):

Contraindications

Contraindications include hypersensitivity to abiraterone acetate. Although documents state that it should not be taken by women who are or who may become pregnant,[5][10] there is no medical reason that any woman should take it. Women who are pregnant should not even touch the pills unless they are wearing gloves.[10] Other cautions include severe baseline hepatic impairment, mineralocorticoid excess, cardiovascular disease including heart failure and hypertension, uncorrected hypokalaemia, and adrenocorticoid insufficiency.[9]

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.[9][10] 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.[9][10]

Mechanism of action

Abiraterone, the active metabolite of abiraterone acetate, inhibits CYP17A1, which manifests as two enzymes, 17α-hydroxylase (IC50 = 2.5 nM) and 17,20-lyase (IC50 = 15 nM) (six-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase)[11] that are expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 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.[12] DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of androgens such as DHEA, testosterone, and dihydrotestosterone (DHT).

Abiraterone also acts as a partial antagonist of androgen receptors, and as an inhibitor of the enzymes 3β-hydroxysteroid dehydrogenase, CYP11B1 (steroid 11β-hydroxylase), and other CYP450s (e.g., CYP1A2, CYP2C9, and CYP3A4).[9][13]

Abiraterone acetate reduces serum testosterone levels to less than 1 ng/dL (i.e., undetectable),[11] and decreases the weights of the prostate gland, seminal vesicles, and testes, in accordance with its antiandrogen action.[14]

Pharmacokinetics

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 metabolised 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.[10]

History

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. Starting from the drug ketoconazole, they developed abiraterone, filing a patent in 1993 and publishing the first paper describing it the following year.[15][16] Rights for commercialisation 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.[17] 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.[18]

Abiraterone acetate is licensed by the European Medicines Agency.[19] 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.[20] The use is currently limited to men who have already received one docetaxel-containing chemotherapy regimen.[21][22]

Clinical studies

A phase III study in subjects previously treated with docetaxel started in 2008.[23] In September 2010, an independent panel found that the interim results in patients previously treated with docetaxel were so much better compared to those treated with placebo that it was unethical to keep half the study participants on placebo, and all patients began receiving the drug. Overall survival was increased by 3.9 months in to this study (14.8 months versus 10.9 months for placebo).[24]

A placebo-controlled double-blind randomized phase III study in patients with castration-refractory prostate cancer but who had not received chemotherapy opened to accrual in April 2009.[25][26] 1,088 men received either abiraterone acetate (1000 mg daily) plus prednisone (5 mg twice daily), or placebo plus prednisone. The median radiographic progression-free survival was 16.5 months with abiraterone acetate–prednisone and 8.3 months with prednisone alone (hazard ratio (HR) = 0.53; 95% confidence interval (CI), 0.45 to 0.62; P<0.001). After a median follow-up period of 22.2 months, overall survival was better with abiraterone acetate plus prednisone (median not reached) compared to placebo plus prednisone (27.2 months); HR = 0.75; 95% CI, 0.61 to 0.93; P=0.01).[27]

See also

References

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  7. ↑ 7.0 7.1 7.2 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ EMA assessment of Zytiga (abiraterone)
  20. ↑ "Prostate cancer (metastatic, castration resistant) - abiraterone (following cytoxic therapy): final appraisal determination guidance". NICE guidance. 15 May 2012.
  21. ↑ "NICE technology appraisal guidance [TA259]". NICE guidance. June 2012.
  22. ↑ "NICE appraisal of earlier treatment with abiraterone for prostate cancer". NICE press release. 14 August 2014.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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