|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Metabolism||CYP3A4- and SULT2A1-mediated|
|Biological half-life||12 ± 5 hours|
|Excretion||Faecal (88%), renal (5%)|
|CAS Registry Number|
|Molecular mass||349.509 g/mol|
|(what is this?)|
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 (formerly 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 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.
After an expedited six-month review, abiraterone acetate was approved by the U.S. Food and Drug Administration (FDA) in April 2011. In phase III clinical trials, it extended median survival to 14.8 months versus 10.9 months placebo, and the trial was stopped early because of the successful outcome.
Abiraterone acetate is indicated for use in combination with prednisone as a treatment for metastatic castration-resistant prostate cancer. It has received FDA (28 April 2011), EMA (23 September 2011), MHRA (5 September 2011) and TGA (1 March 2012) approval for this indication. 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).
Common (1-10% frequency):
Uncommon (0.1-1% frequency):
Rare (<0.1% frequency):
- Allergic alveolitis
Contraindications include hypersensitivity to abiraterone acetate in women who are or may become pregnant. Cautions include:
- 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 acetate
Abiraterone acetate is a CYP3A4 substrate and hence should not be administered in patients concurrently on strong CYP3A4 inhibitors or inducers. 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.
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), 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. 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 an antagonist of the androgen receptor (AR) (to some extent) and as an inhibitor of the enzymes 3β-hydroxysteroid dehydrogenase, CYP11B1 (steroid 11β-hydroxylase), and other CYP450s (e.g., CYP1A2, CYP2C9, and CYP3A4).
Abiraterone acetate is able to reduce serum testosterone levels to less than 1 ng/dL (i.e., undetectable), and decreases the weights of the prostate gland, seminal vesicles, and testes, in accordance with its antiandrogen action.
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 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 by feces (~88%) and urine (~5%) with a terminal half life of 12 ± 5 hours.
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. 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. 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.
Abiraterone acetate is licensed by the European Medicines Agency. 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. The use is currently limited to men who have already received one docetaxel-containing chemotherapy regimen.
A phase III trial in subjects previously treated with docetaxel started in 2008. 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.
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. 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.
The first clinical studies were run in 2004. A more recent[when?] 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. However others cautioned in 2008 that it was too early to know whether abiraterone treatment will have long term benefit.
Results of two phase II trials indicate that abiraterone acetate may reduce prostate specific antigen (PSA) levels, as well as shrink tumors. 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. 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. Phase II clinical trials of abiraterone acetate'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.
The results of a small study showed that abiraterone acetate 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.
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 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 improved with abiraterone acetate–prednisone (median not reached, vs. 27.2 months for prednisone alone; HR = 0.75; 95% CI, 0.61 to 0.93; P=0.01).
- Cyproterone acetate
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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.
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- "Mechanism of Action"
- "Coadministration with Prednisone"
- "Dosage & Administration Guide"
- Information about abiraterone for UK patients – Cancer Research UK's CancerHelp UK website