Abiraterone

Therapeutic Class
 Antiandrogen
Indications

Treatment of metastatic, castration-resistant prostate cancer (in combination with prednisone) in patients previously treated with docetaxel.
Adult Doses

Oral:
Prostate cancer, metastatic, castration-resistant: 
1000 mg once daily (in combination with prednisone 5 mg twice daily).
Doses in Renal impairment

No adjustment required
Doses in Hepatic impairment

Mild (Child-Pugh class A): No adjustment required.

Moderate (Child-Pugh class B): 250 mg once daily. Permanently discontinue treatment if ALT and/or AST >5 times the upper limit of normal (ULN) or total bilirubin >3 times ULN.

Severe (Child-Pugh class C): Avoid use.
Contraindications

Hypersensitivity to abiraterone acetate.
Pregnant women.
Warnings / Precautions

Hazardous agent: Use appropriate precautions for handling and disposal.

Adrenocortical insufficiency, Hepatotoxicity, Hepatic impairment,  Mineralocorticoid excess, Cardiovascular disease.
Adverse Reactions

Cardiovascular: Edema, Hypertension, arrhythmia, chest pain/discomfort, heart failure

Endocrine & metabolic: Triglycerides increased, hypokalemia, hypophosphatemia, hot flush

Gastrointestinal: Diarrhea, Dyspepsia

Genitourinary: Urinary tract infection, Polyuria, nocturia

Hepatic: AST increased, ALT increased, Bilirubin increased

Neuromuscular & skeletal: Joint swelling/discomfort, muscle discomfort

Respiratory: Cough, Upper respiratory infection
Food Interactions

Must be administered on an empty stomach (administer at least 1 hour before and 2 hours after any food)  (otherwise will increase systemic exposure).
Mechanism of Actions

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. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone.
Pharmacodynamics

Distribution: Vdss: 19,669 ± 13,358 L

Protein binding: >99%; to albumin and alpha1-acid glycoprotein

Metabolism: Abiraterone acetate is hydrolyzed to the active metabolite abiraterone; further metabolized to inactive metabolites abiraterone sulphate and N-oxide abiraterone sulphate via CYP3A4 and SULT2A1

Bioavailability: Systemic exposure is increased by food

Half-life elimination: 12 ± 5 hours

Time to peak: 2 hours

Excretion: Feces (~88%); urine (~5%)
Monitoring

ALT, AST, and bilirubin prior to treatment, every 2 weeks for 3 months and monthly thereafter.

If baseline moderate hepatic impairment (Child-Pugh class B), monitor ALT, AST, and bilirubin prior to treatment, weekly for the first month, every 2 weeks for 2 months then monthly thereafter. If hepatotoxicity develops during treatment (and only after therapy is interrupted and liver function tests have returned to safe levels), monitor ALT, AST, and bilirubin every 2 weeks for 3 months and monthly thereafter.Monitoring of testosterone levels is not necessary.
Monitor for signs and symptoms of adrenocorticoid insufficiency; monthly for hypertension, hypokalemia, and fluid retention.
Administration

Administer orally on an empty stomach, at least 1 hour before and 2 hours after food. Swallow tablets whole with water.
Pregnancy Category

X: Drug Pregnancy Category Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Lactation

Excretion in breast milk unknown/not recommended.
ATC Classification
 L02BX03
GenericPedia Classification
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