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Abiraterone acetate

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Abiraterone acetate
Clinical data
License data
Pregnancy
category
  • X
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding>99%
MetabolismCYP3A4- and SULT2A1-mediated
Elimination half-life12 ± 5 hours
ExcretionFecal (88%), renal (5%)
Identifiers
  • (3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.149.063 Edit this at Wikidata
Chemical and physical data
FormulaC24H31NO
Molar mass349.509 g/mol g·mol−1
3D model (JSmol)
  • 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 checkY
  • Key:GZOSMCIZMLWJML-VJLLXTKPSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Abiraterone (tradename Zytiga) is a drug used in castration-resistant prostate cancer (formerly hormone-resistant or hormone-refractory prostate cancer) (prostate cancer not responding to androgen deprivation or treatment with antiandrogens). After an expedited six-month review, abiraterone was approved by the U.S. Food and Drug Administration (FDA) in April 2011.[1][2] In Phase III trials, it extended median survival to 14.8 months versus 11.2 months placebo, and the trial was stopped because of the successful outcome. A course of treatment costs $40,000.[3]

History

This drug was initially discovered in the Cancer Research UK Centre for Cancer Therapeutics[4] at the Institute of Cancer Research in London. Rights for commercialization of the drug were assigned to BTG plc, a UK company that manages commercialization activity in pharmaceuticals. BTG then licensed the product to Cougar Biotechnology which began development of the commercial product.[5] In 2009, Cougar was acquired by Johnson & Johnson which is currently conducting clinical trials on abiraterone.[6]

Mechanism of action

Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy derivatives by its 17 α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its C17,20 lyase activity.[7] DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone.

Pharmacokinetics

After oral administration, abiraterone acetate, the prodrug form present 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 in empty stomach. The drug is highly protein bound (>99%), and is metabolised in the liver by CYP3A4 and SULT2A1 to inactive metabolites. The drug is excreted by feces (~88%) and urine (~5%) with a terminal half life of 12 ± 5 hours.[8]

Clinical studies

A Phase III trial in subjects previously treated with docetaxel started in 2008.[9] A placebo-controlled randomized phase III clinical trial in patients with castration-refractory prostate cancer who are chemotherapy-naive opened to accrual in April 2009.[10] Encouraging results to be presented in Oct 2010.[11]

In September 2010, an independent panel found that the interim results of the phase three clinical trial, in previously treated docetaxel patients, were so successful that it would have been unethical to keep half the trial participants on placebo, and all patients began receiving the drug.[2] Overall survival was increased by 3.9 months according to this trial. A final FDA decision on approval of abiraterone is expected by June 2011. Additionally, J&J will be allowed to make abiraterone available to some prostate cancer patients before the FDA approves the drug.[2]

The first study run at the Royal Marsden Hospital, London, in patients who had not received chemotherapy reported in 2007 that abiraterone acetate induced decline in prostate specific antigen (PSA) in up to 70% of patients as well as radiological shrinkage of tumors, symptom improvement, normalization of lactate dehydrogenase.[12] However others cautioned in 2008 that it was too early to know whether abiraterone treatment will have long term benefit.[13][14]

Results of two Phase II trials indicate that abiraterone may reduce prostate specific antigen (PSA) levels, as well as shrink tumors.[15] Many of the 21 men in the Phase II trial reported significant improvements in their quality of life and several were able to stop taking morphine, used to control the pain caused after the cancer spread into their bones.[16] On average, progression-free survival (PFS) was prolonged by 161 days in patients which had been treated with chemotherapy, and by 236 days in chemotherapy naive patients.[17] Phase II clinical trials of abiraterone's effectiveness in patients who have not yet received treatment with chemotherapy (33 patients) found a median time to PSA progression of 48 weeks. Another phase II trial in patients who had failed prior treatment with docetaxel (47 patients) showed a median time to PSA progression of 24 weeks.[18]

A Phase I/II clinical trial evaluating abiraterone acetate in advanced breast cancer patients is also underway.[11]

Media Coverage

On 19th August 2011, the BBC reported the possibility that Abdelbaset al-Megrahi is being kept alive by drugs not available in the UK. Professor Roger Kirby suggested that al-Megrahi is being treated with abiraterone.[19] Professor Kirby stated: "Unfortunately I don't think they were aware of these new treatments such as abiraterone, which is transforming the prospects for patients with advanced prostate cancer. They just are living longer and longer. It's unknown how long this man will live and with extra additional new treatments it could have been predicted that he might be alive."[20]

See also

  • MDV3100, an oral anti-androgen currently being tested in a phase III clinical trial for use in hormone-refractory prostate cancer (HRPC)

References

  1. ^ "FDA approves Zytiga for late-stage prostate cancer". Press Release. U.S. Food and Drug Administration. 2011-04-28. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  2. ^ a b c J&J Expands Options For Prostate Cancer, Investor's Business Daily, September 24, 2010
  3. ^ New Drugs Fight Prostate Cancer, but at High Cost By ANDREW POLLACK, New York Times, June 27, 2011
  4. ^ New results for prostate cancer drug abiraterone, Cancer Research UK Science Update blog, May 2009
  5. ^ "Abiraterone Acetate (CB7630)". Research and Development Pipeline. Cougar Biotechnology, Inc. Retrieved 2008-08-20.
  6. ^ "Johnson & Johnson Announces Definitive Agreement to Acquire Cougar Biotechnology, Inc". Press Release. Cougar Biotechnology, Inc. 2009-05-11. Retrieved 2009-06-03.
  7. ^ Attard G, Belldegrun AS, de Bono JS (2005). "Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer". BJU Int. 96 (9): 1241–6. doi:10.1111/j.1464-410X.2005.05821.x. PMID 16287438. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ "Zytiga prescribing information" (pdf). Centocor Ortho Biotech Inc. 2011-04-01. Retrieved 2011-05-26. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  9. ^ "NCT00638690". ClinicalTrials.gov. Retrieved 2008-08-22. Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  10. ^ "NCT00887198". ClinicalTrials.gov. Retrieved 2009-12-29. Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  11. ^ a b "BTG and Ortho Biotech's Prostate Cancer Trial Unblinded". News Highlights. Genetic Engineering & Biotechnology News. 2010-09-10. Retrieved 2011-05-26.
  12. ^ Attard G, Reid AHM, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS (2008). "Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven". Journal of Clinical Oncology. 26 (28): 4563. doi:10.1200/JCO.2007.15.9749. PMID 18645193. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  13. ^ Cole A (2008). "Cancer expert doubts claims about prostate cancer trial". BMJ. 337: a979. doi:10.1136/bmj.a979. PMID 18653636.
  14. ^ Attard G, Reid AH, Dearnaley D, De Bono JS (2008). "New prostate cancer drug: Prostate cancer's day in the sun". BMJ. 337: a1249. doi:10.1136/bmj.a1249. PMID 18694888.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ "Hormone inhibitor promising for hard-to-treat prostate cancer". Press release. European Society for Medical Oncology. 2007-07-08. Retrieved 2008-07-22.
  16. ^ "Drug for deadly prostate cancer". Health. BBC NEWS. 2008-07-21. Retrieved 2008-08-20. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  17. ^ PMID 19223900
  18. ^ "Latest cancer research Phase II results demonstrate efficacy of abiraterone acetate plus prednisone for castration-resistant prostate cancer". Insider News. ecancermedicalscience. 2010-92-17. Retrieved 2011-05-26. {{cite web}}: Check date values in: |date= (help); Cite has empty unknown parameter: |coauthors= (help)
  19. ^ Cancer Research UK
  20. ^ BBC Online

News reports

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