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アビラテロン

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Abiraterone is a drug used in combination with prednisone in metastatic castration-resistant prostate cancer (formerly hormone-resistant or hormone-refractory prostate cancer) -- i.e., prostate cancer not responding to androgen deprivation or treatment with antiandrogens. It is formulated as the prodrug abiraterone acetate and marketed under the trade name Zytiga. Cadila Pharmaceuticals has recently started marketing Abiraterone acetate under the trade name Abretone.

アビラテロン
IUPAC命名法による物質名
臨床データ
販売名 Zytiga
Drugs.com monograph
MedlinePlus a611046
ライセンス US FDA:リンク
胎児危険度分類
  • AU: D
  • US: X
法的規制
投与経路 Oral
薬物動態データ
血漿タンパク結合>99%
代謝CYP3A4- and SULT2A1-mediated
半減期12 ± 5 hours
排泄Faecal (88%), renal (5%)
識別
CAS番号
 154229-19-3 ×
ATCコード L02BX03 (WHO)
PubChem CID: 132971
ChemSpider 117349 チェック
UNII G819A456D0 チェック
ChEMBL CHEMBL254328 チェック
化学的データ
化学式C24H31NO
分子量349.509 g/mol
テンプレートを表示

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 10.9 months placebo, and the trial was stopped because of the successful outcome.

Medical uses

It is indicated for use in combination with prednisone as a treatment for metastatic castration-resistant prostate cancer.[3][4][5][6] It has received FDA (28 April 2011), EMA (23 September 2011), MHRA (5 September 2011) and TGA (1 March 2012) approval for this indication.[3][4][5][6] 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 has commenced).[7]

Adverse effects

Adverse effects by frequency:[3][4][5][6][8]
Very common (>10% frequency):

Common (1-10% frequency):

  • Hypertriglyceridaemia
  • Sepsis
  • Cardiac failure
  • Angina pectoris
  • Arrhythmia
  • Atrial fibrillation
  • Tachycardia
  • Dyspepsia (indigestion)
  • Rash
  • Alanine aminotransferase increased
  • Aspartate aminotransferase increased
  • Fractures
  • Hematuria

Uncommon (0.1-1% frequency):

Rare (<0.1% frequency):

Contraindications

Contraindications include hypersensitivity to abiraterone in women who are or may become pregnant. Cautions include:[8]

  • Patients with severe baseline hepatic impairment
  • Patients with Mineralocorticoid excess
  • Patients with cardiovascular disease, including heart failure and hypertension
  • Patients with uncorrected hypokalaemia
  • Patients with adrenocorticoid insufficiency
  • Hepatotoxicity that may result from treatment with abiraterone

Interactions

Abiraterone is a CYP3A4 substrate and hence should not be administered in patients concurrently on strong CYP3A4 inhibitors or inducers.[8] Likewise it inhibits CYP1A2, CYP2C9 and CYP3A4 and hence should not be given to patients concurrently being treated with substrates of any of these enzymes that have a narrow therapeutic index.[8]

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.[9] 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 on an empty stomach at least two hours before or one hour 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 by feces (~88%) and urine (~5%) with 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 within the Institute of Cancer Research in London set out to develop drug treatments for prostate cancer. Starting from the drug ketoconazole, they developed abiraterone as a more effective variant, filing a patent in 1993 and publishing the first paper describing the drug the following year.[11][12] Rights for commercialisation of the drug were assigned to BTG plc, a UK-based specialist healthcare company. BTG then licenced the product to Cougar Biotechnology which began development of the commercial product.[13] 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.[14]

In the UK, despite being licensed by the European Medicines Agency,[15] the drug is not currently[いつ?] available for routine use on the NHS. In February 2012, the National Institute for Health and Clinical Excellence (NICE) issued[16] preliminary guidance that the drug will not be made available on cost-effectiveness grounds, but this decision is open to consultation.[17] The decision was reversed in May 2012.[18][19][20][21][22][23][24]

Clinical studies

A phase III trial in subjects previously treated with docetaxel started in 2008.[25] A placebo-controlled randomised phase III clinical trial in patients with castration-refractory prostate cancer who are chemotherapy-naive opened to accrual in April 2009.[26][27]

In September 2010, an independent panel found that the interim results of the phase III 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 (14.8 months versus 10.9 months for placebo). It was approved by the FDA in April 2011.[28]

The first clinical studies were run in 2004.[29] A more recent[いつ?] study 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, normalisation of lactate dehydrogenase.[30] However others cautioned in 2008 that it was too early to know whether abiraterone treatment will have long term benefit.[31][32]

Results of two phase II trials indicate that abiraterone may reduce prostate specific antigen (PSA) levels, as well as shrink tumors.[33] 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.[34] 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.[35] 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.[36]

A phase I/II clinical trial evaluating abiraterone acetate in advanced breast cancer patients is also underway.[27][37]

The results of a small study showed that abiraterone eliminated or nearly eliminated tumors in about one-third of men whose disease had not yet spread beyond the prostate gland but was considered likely to do so.[38][39][40]

A double-blind phase III randomised controlled trial investigated the use of abiraterone acetate in men with metastatic castration-resistant prostate cancer with no previous chemotherapy. They randomly assigned 1,088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The median radiographic progression-free survival was 16.5 months with abiraterone–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 improved with abiraterone–prednisone (median not reached, vs. 27.2 months for prednisone alone; HR = 0.75; 95% CI, 0.61 to 0.93; P=0.01).[41]

See also

References

  1. ^ "FDA approves Zytiga for late-stage prostate cancer" (Press release). Food and Drug Administration (FDA). 28 April 2011.
  2. ^ a b J&J Expands Options For Prostate Cancer, Investor's Business Daily, 24 September 2010
  3. ^ a b c “ZYTIGA (abiraterone acetate) tablet [Janssen Biotech, Inc.]”. DailyMed. Janssen Biotech, Inc. (2013年9月). 2014年1月24日閲覧。
  4. ^ a b c “Zytiga : EPAR - Product Information” (PDF). European Medicines Agency. Janssen-Cilag International N.V. (2013年10月29日). 2014年1月24日閲覧。
  5. ^ a b c “Zytiga 250 mg tablets - Summary of Product Characteristics”. electronic Medicines Compendium. Janssen-Cilag Ltd (2014年1月21日). 2014年1月24日閲覧。
  6. ^ a b c “ZYTIGA® abiraterone acetate PRODUCT INFORMATION” (PDF). TGA eBusiness Services. JANSSEN-CILAG Pty Ltd (2012年3月1日). 2014年1月24日閲覧。
  7. ^ “Pharmaceutical Benefits Scheme - ABIRATERONE”. Pharmaceutical Benefits Scheme. 2014年1月24日閲覧。
  8. ^ a b c d “Zytiga (abiraterone) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. 2014年1月24日閲覧。
  9. ^ 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 Int. 96 (9): 1241–6. doi:10.1111/j.1464-410X.2005.05821.x. PMID 16287438. 
  10. ^ “Zytiga prescribing information” (pdf). Janssen Biotech (2012年5月). 2012年5月19日閲覧。
  11. ^ Scowcroft H (2011年9月21日). “Where did abiraterone come from?”. Cancer Research UK. 2011年9月28日閲覧。
  12. ^ “A new way to treat prostate cancer: The story of abiraterone”. The Institute of Cancer Research (2012年9月10日). 2012年11月12日閲覧。
  13. ^ “Abiraterone Acetate (CB7630)”. Cougar Biotechnology. 2008年9月7日時点のオリジナルよりアーカイブ。2008年8月20日閲覧。
  14. ^ "Johnson & Johnson Announces Definitive Agreement to Acquire Cougar Biotechnology, Inc" (Press release). Cougar Biotechnology. 11 May 2009. 2009年5月29日時点のオリジナルよりアーカイブ。2009年6月3日閲覧。 {{cite press release2}}: 不明な引数|deadurl=は無視されます。（もしかして：|url-status=） (説明)
  15. ^ EMA assessment of Zytiga (abiraterone)
  16. ^ "NICE consults on a new treatment for prostate cancer" (Press release). United Kingdom National Institute for Health and Clinical Excellence. 2 February 2012. 2012年2月2日閲覧。
  17. ^ Scowcroft H (2012年2月2日). “Why today's prostate drug decision makes no sense”. Cancer Research UK - Science Update blog. 2012年2月2日閲覧。
  18. ^ "Prostate cancer (metastatic, castration resistant) - abiraterone (following cytoxic therapy): final appraisal determination guidance". NICE guidance. 15 May 2012.
  19. ^ NHS 'OK' for prostate cancer drug Zytiga - PubMed Health
  20. ^ “Prostate drug abiraterone 'set for NHS use'”. BBC News. (2012年5月16日). http://www.bbc.co.uk/news/health-18076137 
  21. ^ Bates, Claire (2012年5月15日). “England benefits from NHS postcode lottery at long last - as prostate cancer wonder drug looks set for approval south of border but not in Scotland”. Daily Mail (London). http://www.dailymail.co.uk/health/article-2144903/Prostate-cancer-drug-extend-patients-lives-months-set-NHS-use-drug-watchdog-reverses-ban.html 
  22. ^ “Prostate cancer: health watchdog reverses NHS guidance on drug”. The Guardian (London). (2012年5月16日). http://www.guardian.co.uk/society/2012/may/16/prostate-cancer-nhs-drug-abiterone 
  23. ^ “Nice 'to reverse ban on prostate cancer drug'”. The Daily Telegraph (London). (2012年5月14日). http://www.telegraph.co.uk/health/healthnews/9264059/Nice-to-reverse-ban-on-prostate-cancer-drug.html 
  24. ^ Express.co.uk - Home of the Daily and Sunday Express | Health :: NHS ban on pill to treat prostate cancer is lifted
  25. ^ “NCT00638690”. ClinicalTrials.gov. 2008年8月21日時点のオリジナルよりアーカイブ。2008年8月22日閲覧。 “Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy”
  26. ^ “NCT00887198”. ClinicalTrials.gov. 2009年12月29日閲覧。 “Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer”
  27. ^ a b “BTG and Ortho Biotech's Prostate Cancer Trial Unblinded”. Genetic Engineering & Biotechnology News (2010年9月10日). 2011年5月26日閲覧。
  28. ^ “FDA Approval for Abiraterone Acetate”. Template:Cite webの呼び出しエラー：引数 accessdate は必須です。
  29. ^ O'Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M, Harland S, Robbins A, Halbert G, Nutley B, Jarman M (June 2004). “Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer”. Br. J. Cancer 90 (12): 2317–25. doi:10.1038/sj.bjc.6601879. PMC 2409523. PMID 15150570. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409523/. 
  30. ^ 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): 4563–71. doi:10.1200/JCO.2007.15.9749. PMID 18645193. 
  31. ^ Cole A (2008). “Cancer expert doubts claims about prostate cancer trial”. BMJ 337: a979. doi:10.1136/bmj.a979. PMID 18653636. 
  32. ^ 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. 
  33. ^ "Hormone inhibitor promising for hard-to-treat prostate cancer" (Press release). European Society for Medical Oncology. 8 July 2007. 2008年6月13日時点のオリジナルよりアーカイブ。2008年7月22日閲覧。 {{cite press release2}}: 不明な引数|deadurl=は無視されます。（もしかして：|url-status=） (説明)
  34. ^ Warry, Richard (2008年7月21日). “Drug for deadly prostate cancer”. BBC News Online. オリジナルの2008年8月30日時点におけるアーカイブ。. http://web.archive.org/web/20080830221552/http://news.bbc.co.uk/2/hi/health/7502238.stm 2008年8月20日閲覧。 
  35. ^ Ang, J. E.; Olmos, D.; De Bono, J. S. D. (March 2009). “CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer”. Br. J. Cancer 100 (5): 671–675. doi:10.1038/sj.bjc.6604904. PMC 2653756. PMID 19223900. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653756/.  編集
  36. ^ “Latest cancer research Phase II results demonstrate efficacy of abiraterone acetate plus prednisone for castration-resistant prostate cancer”. ecancermedicalscience (2010-92-17). 2011年5月26日閲覧。
  37. ^ CRUKD/08/044 A CR-UK Phase I/II trial of abiraterone acetate in patients with ER+, PR+ or AR+ refractory metastatic breast cancer : Cancer Research UK
  38. ^ Andrew Pollack (2012年5月17日). “Trial Supports Earlier Use of a Prostate Cancer Drug”. The New York Times. http://www.nytimes.com/2012/05/17/health/zytiga-a-prostate-cancer-drug-does-well-in-trial.html. "A new drug used to treat advanced prostate cancer may also help men if used early in the course of the disease, before an operation, researchers reported Wednesday.
    In a small clinical trial, six months of treatment with the drug, Johnson & Johnson's Zytiga, added to standard therapy, eliminated or nearly eliminated tumors in about one-third of men whose disease had not yet spread beyond the prostate gland but was considered likely to do so."     
  39. ^ Jennifer Corbett Dooren; Peter Loftus (2012年5月16日). “Study: J&J's Zytiga Can Eliminate Some Prostate Tumors”. The Wall Street Journal. http://online.wsj.com/article/SB10001424052702303360504577408700087593244.html 
  40. ^ "ZYTIGA (abiraterone acetate) Data to be Presented at 2012 American Society of Clinical Oncology (ASCO) Annual Meeting" (Press release). Janssen Research & Development. 18 May 2012.
  41. ^ 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 (December 2012). “Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy”. N. Engl. J. Med. 368 (2): 138–48. doi:10.1056/NEJMoa1209096. PMC 3683570. PMID 23228172. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/. 


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