Usage
Abiraterone acetate is prescribed for the treatment of metastatic castration-resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (mCSPC). It is classified as an antineoplastic agent, specifically a CYP17 inhibitor. It works by inhibiting the enzyme CYP17, which is involved in the production of androgens (male hormones like testosterone) in the testes, adrenal glands, and tumor tissue. By blocking this enzyme, abiraterone acetate reduces androgen levels, thereby slowing the growth of prostate cancer cells that rely on these hormones.
Alternate Names
The international nonproprietary name (INN) is abiraterone acetate. Brand names include Zytiga® and Yonsa®.
How It Works
Pharmacodynamics: Abiraterone acetate is a prodrug that is rapidly converted to its active metabolite, abiraterone. Abiraterone inhibits CYP17, a key enzyme in androgen biosynthesis. This inhibition occurs in the testes, adrenal glands, and even within the tumor itself. Consequently, it reduces the production of testosterone and other androgens, leading to decreased levels of these hormones in the body. This deprivation of androgens suppresses the growth of prostate cancer.
Pharmacokinetics:
- Absorption: Abiraterone acetate is administered orally and absorption is significantly increased when taken with food. Therefore, it’s crucial to administer the medication on an empty stomach (no food for at least two hours before and one hour after intake).
- Metabolism: It is rapidly hydrolyzed by esterases to its active metabolite, abiraterone. Abiraterone is further metabolized primarily by CYP3A4 to inactive metabolites (abiraterone sulfate and N-oxide abiraterone sulfate).
- Elimination: Primarily eliminated via hepatic (liver) routes through feces and to a lesser extent via renal (kidney) excretion through urine.
Mode of Action: Abiraterone specifically targets and inhibits the CYP17 enzyme complex (17α-hydroxylase/C17,20-lyase), effectively blocking the production of androgens at three different levels: in the testes, adrenal glands, and the prostate tumor itself.
Receptor Binding, Enzyme Inhibition: Abiraterone acts through enzyme inhibition, specifically targeting CYP17. It does not directly bind to androgen receptors.
Elimination Pathways: Primarily hepatic, with a smaller fraction via renal excretion. CYP3A4 plays a major role in abiraterone metabolism.
Dosage
Standard Dosage
Adults:
- mCRPC: 1000 mg (four 250 mg tablets or two 500 mg tablets) once daily, taken orally on an empty stomach with prednisone 5 mg twice daily.
- mCSPC: 1000 mg (four 250 mg tablets or two 500 mg tablets) once daily, taken orally on an empty stomach with prednisone 5 mg once daily.
- Micronized Abiraterone Acetate (Yonsa®): 500 mg (four 125 mg tablets) once daily, taken orally with methylprednisolone 4 mg twice daily.
Children: Use is not recommended.
Special Cases:
- Elderly Patients: No specific dose adjustment is routinely recommended, although close monitoring is advised.
- Patients with Renal Impairment: No dose adjustment is necessary.
- Patients with Hepatic Dysfunction:
- Mild Impairment (Child-Pugh A): No dose adjustment is necessary.
- Moderate Impairment (Child-Pugh B): Starting dose reduced to 250 mg once daily. Close monitoring of liver function tests is crucial.
- Severe Impairment (Child-Pugh C): Abiraterone acetate is contraindicated.
- Patients with Comorbid Conditions: Caution is advised in patients with pre-existing cardiovascular disease, hypertension, diabetes, adrenal or pituitary gland disorders, or those at risk for hypokalemia.
Clinical Use Cases
Abiraterone acetate is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest. Its use is specifically confined to the treatment of mCRPC and mCSPC as an anticancer agent in conjunction with prednisone or methylprednisolone.
Dosage Adjustments
Dose adjustments may be necessary based on individual patient tolerability, the co-administration of strong CYP3A4 inducers (increase abiraterone dose frequency during co-administration), or the development of hepatotoxicity during treatment (interrupt treatment until recovery and consider reducing dose upon re-initiation).
Side Effects
Common Side Effects
- Fluid retention (peripheral edema)
- Fatigue
- Hot flashes
- Joint pain or swelling
- Urinary tract infection
- Diarrhea
- Cough
- Upper respiratory infection
- Hypokalemia
- Hypertension
- Hyperglycemia
Rare but Serious Side Effects
- Hepatotoxicity (liver damage)
- Adrenal insufficiency
- Cardiac arrhythmias (QT prolongation)
- Fractures
- Severe hypoglycemia (particularly in patients with diabetes)
Long-Term Effects
- Osteoporosis (bone thinning)
- Cardiovascular complications
Adverse Drug Reactions (ADR)
- Adrenocortical insufficiency
- Hepatotoxicity (requiring immediate discontinuation)
- Severe hyperglycemia
- Hypokalemia
- Hypertension
- Cardiac events (e.g., arrhythmias, heart failure).
Contraindications
- Severe hepatic impairment (Child-Pugh C)
- Pregnancy (can cause fetal harm)
- Women of childbearing potential who are not using effective contraception
Drug Interactions
- CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort): Reduce abiraterone exposure. Avoid co-administration or adjust abiraterone dosage.
- CYP3A4 inhibitors (e.g., ketoconazole): No clinically significant effect.
- CYP2D6 substrates (e.g., dextromethorphan, thioridazine): Abiraterone can increase their levels. Avoid co-administration or adjust the dosage of the CYP2D6 substrate.
- CYP2C8 substrates (e.g., pioglitazone, repaglinide): Abiraterone can increase their levels. Monitor for toxicity and consider dose adjustment, especially for those with a narrow therapeutic index.
- Radium Ra 223: Concomitant use increases the risk of fractures and death.
- Spironolactone: May increase PSA levels; co-administration is not recommended.
- Oral anticoagulants (e.g., warfarin): Close monitoring is recommended due to potential interaction, though specific dose adjustment guidelines are not established.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: X (contraindicated)
- Fetal Risks: Abiraterone can cause fetal harm and pregnancy loss. Women who are pregnant or may become pregnant should not handle the drug.
- Breastfeeding: Not recommended. It is unknown if abiraterone passes into breast milk.
Drug Profile Summary
- Mechanism of Action: CYP17 inhibitor, suppressing androgen production.
- Side Effects: Fluid retention, fatigue, hot flashes, joint pain, hypokalemia, hypertension, hepatotoxicity, adrenal insufficiency, cardiac arrhythmias.
- Contraindications: Severe hepatic impairment, pregnancy, women of childbearing potential not using effective contraception.
- Drug Interactions: CYP3A4 inducers/inhibitors, CYP2D6 and CYP2C8 substrates, radium Ra 223, spironolactone.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
- Dosage: mCRPC: 1000 mg once daily with prednisone 5 mg BID; mCSPC: 1000 mg once daily with prednisone 5 mg daily. Micronized: 500 mg once daily with methylprednisolone 4 mg BID.
- Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), blood pressure, serum potassium, fluid retention, cardiac function, blood glucose (in diabetic patients).
Popular Combinations
- Abiraterone acetate + prednisone (for mCRPC and mCSPC)
- Abiraterone acetate + methylprednisolone (for mCRPC, micronized formulation)
- Concurrent GnRH analogue or prior bilateral orchiectomy is usually recommended.
Precautions
- General Precautions: Monitor liver function, blood pressure, serum potassium, and fluid retention. Assess cardiac function and blood glucose regularly, especially in patients with pre-existing conditions.
- Pregnant Women: Absolutely contraindicated. Should not handle the medication.
- Breastfeeding Mothers: Avoid breastfeeding.
- Children & Elderly: Not recommended for children. Monitor elderly patients closely.
- Lifestyle Considerations: Advise patients to avoid grapefruit juice, which may inhibit CYP3A4 and increase abiraterone exposure.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Abiraterone Acetate?
A: For mCRPC, 1000 mg once daily with prednisone 5 mg twice daily. For mCSPC, 1000 mg once daily with prednisone 5 mg once daily. For the micronized formulation (Yonsa®), 500 mg once daily with methylprednisolone 4 mg twice daily.
Q2: Should Abiraterone Acetate be taken with food?
A: No, it should be taken on an empty stomach (no food for at least two hours before and one hour after). Taking it with food significantly increases absorption and may lead to increased side effects.
Q3: What are the most common side effects of Abiraterone Acetate?
A: Common side effects include fluid retention, fatigue, hot flashes, joint pain, urinary tract infections, diarrhea, cough, upper respiratory infections, hypokalemia, hypertension, and hyperglycemia.
Q4: How does Abiraterone Acetate interact with other medications?
A: It can interact with CYP3A4 inducers (reduce its effectiveness) and inhibitors, CYP2D6 and CYP2C8 substrates (increase their levels), radium Ra 223 (increased risk of fractures), and spironolactone. Consult a drug interaction checker for a comprehensive list.
Q5: Can Abiraterone Acetate be used in patients with liver problems?
A: It can be used in patients with mild hepatic impairment. Dose reduction is needed for moderate impairment. It’s contraindicated in severe hepatic impairment.
A: Serious side effects include hepatotoxicity, adrenal insufficiency, cardiac arrhythmias (QT prolongation), severe hypoglycemia, and fractures.
Q7: Is Abiraterone Acetate safe during pregnancy or breastfeeding?
A: No, it is contraindicated in pregnancy and should be avoided during breastfeeding.
Q8: What monitoring is required for patients taking Abiraterone Acetate?
A: Regular monitoring of liver function tests, blood pressure, serum potassium, fluid retention, cardiac function, and blood glucose (especially for diabetics) is essential.
Q9: What is the mechanism of action of Abiraterone Acetate?
A: It inhibits the CYP17 enzyme, which is crucial for androgen biosynthesis, effectively reducing androgen levels in the body.
Q10: What is the difference between Zytiga and Yonsa?
A: Zytiga is a standard formulation of abiraterone acetate requiring 1000mg dosage. Yonsa is a micronized formulation of abiraterone acetate requiring 500mg dosage. Both are taken once a day. Both are taken with corticosteroids. Yonsa is taken with methylprednisolone twice a day, while Zytiga is taken with prednisone twice a day.
