Abiraterone acetate

Abiraterone acetate
Clinical data
Trade names Zytiga
AHFS/Drugs.com Monograph
MedlinePlus a611046
License data
Pregnancy
category
  • AU: D
  • US: X (Contraindicated)
Routes of
administration		 Oral (tablets)
ATC code L02BX03 (WHO)
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%[1]
Metabolism Esterases, CYP3A4, SULT2A1[1]
Biological half-life 12 ± 5 hours[1]
Excretion Feces (88%), urine (5%)[1]
Identifiers
CAS Number 154229-19-3 N
PubChem (CID) 132971
IUPHAR/BPS 6745
ChemSpider 117349 YesY
UNII G819A456D0 YesY
ChEMBL CHEMBL254328 YesY
Chemical and physical data
Formula C24H31NO
Molar mass 349.509 g/mol
3D model (Jmol) Interactive image
 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.[2][3] 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.[4]

Medical uses

Abiraterone acetate is indicated for use in combination with prednisone as a treatment for metastatic castration-resistant prostate cancer.[5][6][7][8] It has received FDA (28 April 2011), EMA (23 September 2011), MHRA (5 September 2011) and TGA (1 March 2012) approval for this indication.[5][6][7][8] 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).[9]

Adverse effects

Adverse effects by frequency:[5][6][7][8][10]
Very common (>10% frequency):

Common (1-10% frequency):

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,[6][11] 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.[11] Other cautions include severe baseline hepatic impairment, mineralocorticoid excess, cardiovascular disease including heart failure and hypertension, uncorrected hypokalaemia, and adrenocorticoid insufficiency.[10]

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.[10][11] 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.[10][11]

Mechanism of action

Abiraterone—the active metabolite

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)[12] 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.[13] 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 the androgen receptor (AR), and as an inhibitor of the enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD), CYP11B1 (steroid 11β-hydroxylase), and other CYP450s (e.g., CYP1A2, CYP2C9, and CYP3A4).[10][14] In addition to abiraterone itself, part of the activity of the drug has been found to be due to a more potent active metabolite, Δ4-abiraterone (D4A), which is formed from abiraterone by 3β-HSD.[15] D4A is an inhibitor of CYP17A1, 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, and 5α-reductase, and has also been found to act as a competitive antagonist of the AR reportedly comparable to the potent antagonist enzalutamide.[15] However, the initial 5α-reduced metabolite of D4A, 3-keto-5α-abiraterone, is an agonist of the AR, and promotes prostate cancer progression.[16] Its formation can be blocked by the coadministration of dutasteride, a potent and selective 5α-reductase inhibitor.[16]

There has been interest in the use of abiraterone acetate for the treatment of breast cancer due to its ability to lower estrogen levels.[17] However, abiraterone has recently been found to act as a direct agonist of the estrogen receptor, and induces proliferation of human breast cancer cells in vitro.[17] If abiraterone acetate is used in the treatment of breast cancer, it should be combined with an estrogen receptor antagonist like fulvestrant.[17] In spite of its antiandrogen and estrogenic properties, abiraterone acetate does not appear to produce gynecomastia as a side effect.[18]

Abiraterone acetate, via its metabolite abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable),[12][19] and these concentrations are much lower than those achieved by castration (20 ng/dL).[19] The addition of abiraterone acetate to castration was found to reduce levels of DHT by 85%, DHEA by 97–98%, and androstenedione by 77–78% relative to castration alone.[19]

In accordance with its antiandrogen action, abiraterone acetate decreases the weights of the prostate gland, seminal vesicles, and testes.[20]

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.[11]

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.[21][22] 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.[23] 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.[24]

Abiraterone acetate is licensed by the European Medicines Agency.[25] 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.[26] The use is currently limited to men who have already received one docetaxel-containing chemotherapy regimen.[27][28]

Clinical studies

A phase III study in subjects previously treated with docetaxel started in 2008.[29] 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).[30]

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.[31][32] 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).[33]

See also

References

  1. 1 2 3 4 http://meetinglibrary.asco.org/content/114000117-144
  2. ↑ "Drugs@FDA - FDA Approved Drug Products - Zytiga". www.fda.gov. United States Food and Drug Administration. Retrieved 4 March 2016.
  3. ↑ "FDA approves Zytiga for late-stage prostate cancer" (Press release). United States Food and Drug Administration. 2011-04-28.
  4. ↑ "FDA Approval for Abiraterone Acetate".
  5. 1 2 3 "Zytiga (abiraterone acetate) tablet [Janssen Biotech, Inc.]". DailyMed. Janssen Biotech, Inc. September 2013. Retrieved 24 January 2014.
  6. 1 2 3 4 "Zytiga: EPAR - Product Information" (PDF). European Medicines Agency. Janssen-Cilag International N.V. 29 October 2013. Retrieved 24 January 2014.
  7. 1 2 3 "Zytiga 250 mg tablets - Summary of Product Characteristics". electronic Medicines Compendium. Janssen-Cilag Ltd. 21 January 2014. Retrieved 24 January 2014.
  8. 1 2 3 "Zytiga abiraterone acetate product information" (PDF). TGA eBusiness Services. Janssen-Cilag Pty Ltd. 1 March 2012. Retrieved 24 January 2014.
  9. ↑ "Pharmaceutical Benefits Scheme - Abiraterone". Pharmaceutical Benefits Scheme. Retrieved 24 January 2014.
  10. 1 2 3 4 5 "Zytiga (abiraterone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014.
  11. 1 2 3 4 5 "Zytiga prescribing information" (pdf). Janssen Biotech. May 2012. Retrieved 4 March 2016.
  12. 1 2 Neidle S (30 September 2013). Cancer Drug Design and Discovery. Academic Press. pp. 341–342. ISBN 978-0-12-397228-6.
  13. ↑ 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. PMID 16287438.
  14. ↑ Yin L, Hu Q (January 2014). "CYP17 inhibitors--abiraterone, C17,20-lyase inhibitors and multi-targeting agents". Nature Reviews. Urology. 11 (1): 32–42. doi:10.1038/nrurol.2013.274. PMID 24276076.
  15. 1 2 Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, Liu J, Upadhyay SK, Auchus RJ, Sharifi N (July 2015). "Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer". Nature. 523 (7560): 347–51. doi:10.1038/nature14406. PMC 4506215Freely accessible. PMID 26030522.
  16. 1 2 Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, Upadhyay SK, Balk SP, Taplin ME, Auchus RJ, Sharifi N (May 2016). "Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy". Nature. 533 (7604): 547–51. doi:10.1038/nature17954. PMID 27225130.
  17. 1 2 3 Capper 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. PMID 27083183.
  18. ↑ 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. doi:10.1159/000343821. PMID 23128186.
  19. 1 2 3 Small EJ (November 2014). "Can targeting the androgen receptor in localized prostate cancer provide insights into why men with metastatic castration-resistant prostate cancer die?". Journal of Clinical Oncology. 32 (33): 3689–91. doi:10.1200/JCO.2014.57.8534. PMID 25311216. Abiraterone acetate is a prodrug for abiraterone, a CYP17 inhibitor, which has the capacity to lower serum testosterone levels to less than 1 ng/dL (compared with levels closer to 20 ng/dL that are achieved with conventional ADT).19 [...] Relative to LHRHa alone, the addition of abiraterone resulted in an 85% decline in dihydrotestosterone (DHT) levels, a 97% to 98% decline in dehydroepiandrosterone (DHEA) levels, and a 77% to 78% decline in androstenedione levels.
  20. ↑ Tindall DJ, James M (20 April 2009). Androgen Action in Prostate Cancer. Springer Science & Business Media. pp. 748–. ISBN 978-0-387-69179-4.
  21. ↑ Scowcroft H (2011-09-21). "Where did abiraterone come from?". Cancer Research UK. Retrieved 2011-09-28.
  22. ↑ "A new way to treat prostate cancer: The story of abiraterone". The Institute of Cancer Research. 2012-09-10. Retrieved 2012-11-12.
  23. ↑ "Abiraterone Acetate (CB7630)". Cougar Biotechnology. Archived from the original on 7 September 2008. Retrieved 2008-08-20.
  24. ↑ "Johnson & Johnson Announces Definitive Agreement to Acquire Cougar Biotechnology, Inc." (Press release). Cougar Biotechnology. 2009-05-11. Archived from the original on 29 May 2009. Retrieved 2009-06-03.
  25. ↑ EMA assessment of Zytiga (abiraterone)
  26. ↑ "Prostate cancer (metastatic, castration resistant) - abiraterone (following cytoxic therapy): final appraisal determination guidance" Archived February 19, 2013, at the Wayback Machine.. NICE guidance. 15 May 2012.
  27. ↑ "NICE technology appraisal guidance [TA259]". NICE guidance. June 2012.
  28. ↑ "NICE appraisal of earlier treatment with abiraterone for prostate cancer". NICE press release. 14 August 2014.
  29. ↑ "NCT00638690". ClinicalTrials.gov. Archived from the original on 21 August 2008. Retrieved 2008-08-22. Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy
  30. ↑ 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). "Abiraterone and increased survival in metastatic prostate cancer". The New England Journal of Medicine. 364 (21): 1995–2005. doi:10.1056/NEJMoa1014618. PMC 3471149Freely accessible. PMID 21612468.
  31. ↑ "NCT00887198". ClinicalTrials.gov. Retrieved 2009-12-29. Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer
  32. ↑ "BTG and Ortho Biotech's Prostate Cancer Trial Unblinded". Genetic Engineering & Biotechnology News. 2010-09-10. Retrieved 2011-05-26.
  33. ↑ 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). "Abiraterone in metastatic prostate cancer without previous chemotherapy". The New England Journal of Medicine. 368 (2): 138–48. doi:10.1056/NEJMoa1209096. PMC 3683570Freely accessible. PMID 23228172.

External links

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