Abiret

• FDA-Approved Uses:
• Metastatic castration-resistant prostate cancer (mCRPC):
• In combination with prednisone in patients who have received prior chemotherapy containing docetaxel.
• In combination with prednisone in chemotherapy-naïve patients.
• Metastatic high-risk castration-sensitive prostate cancer (mCSPC):
• In combination with prednisone.
• Non-metastatic prostate cancer (specific regional approvals):
• Approved in some countries for patients with high-risk non-metastatic disease.
• Clinically Accepted Off-Label Uses:
• Biochemical recurrent prostate cancer in select patients not candidates for chemotherapy.
• Triple androgen blockade in combination with GnRH analogs and anti-androgens.
• Combination with radiotherapy in high-risk locally advanced prostate cancer (investigational, but supported by emerging data).

• Standard Dose (mCRPC or mCSPC):
• Abiraterone acetate 1,000 mg (four 250 mg tablets) orally once daily on an empty stomach.
• Prednisone 5 mg orally twice daily.
• Administration Instructions:
• Take abiraterone at least 1 hour before or 2 hours after meals (food increases systemic exposure).
• Swallow tablets whole with water.
• Continue androgen deprivation therapy (e.g., GnRH analog) during treatment unless surgically castrated.
• Dose Modifications:
• Hepatic Impairment:
• Child-Pugh A (mild): Use with caution.
• Child-Pugh B (moderate): Reduce dose to 250 mg once daily.
• Child-Pugh C (severe): Contraindicated.
• Hepatotoxicity Management:
• Interrupt treatment if ALT or AST >5× ULN or bilirubin >3× ULN.
• Resume at reduced dose when normalized.
• Renal Impairment:
• No dose adjustment required; minimal renal clearance.
• Elderly:
• No adjustment necessary, but monitor more frequently.

Abiraterone acetate is a prodrug of abiraterone, an irreversible and selective inhibitor of CYP17A1, a critical enzyme in androgen biosynthesis. CYP17A1 catalyzes two sequential steps—17α-hydroxylase and C17,20-lyase activities—required for androgen production in the testes, adrenal glands, and tumor tissues. By blocking these pathways, abiraterone reduces circulating testosterone and intratumoral androgen levels, suppressing prostate cancer growth. The concomitant use of prednisone helps counteract mineralocorticoid excess caused by upstream accumulation of steroid precursors.

• Absorption:
• Oral bioavailability increases ~10-fold when taken with a high-fat meal.
• Time to peak plasma concentration: 2–3 hours in fasting state.
• Distribution:
• Volume of distribution: ~5,630 L.
• Plasma protein binding: ~99% (mainly to albumin).
• Metabolism:
• Rapidly converted in the liver to abiraterone.
• Further metabolized by sulfation and oxidation (primarily via SULT2A1 and CYP3A4).
• Excretion:
• Feces: ~88% (major route), urine: <5%.
• Terminal half-life: ~12 ± 5 hours.
• Steady-State: Reached after ~1 week of daily dosing.

• Pregnancy:
• Category X (contraindicated): Teratogenic in animal studies; not for use in females.
• Women who are pregnant or may become pregnant should not handle crushed/broken tablets.
• Lactation:
• Not indicated for use in females.
• Unknown if excreted in breast milk; avoid exposure.
• Contraception:
• Men with female partners of reproductive potential should use effective contraception during treatment and for 3 weeks after the last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Androgen Biosynthesis Inhibitor (CYP17 Inhibitor)

• Absolute:
• Hypersensitivity to abiraterone or any component of the formulation.
• Severe hepatic impairment (Child-Pugh Class C).
• Use in women who are or may become pregnant.
• Relative:
• Concomitant use with strong CYP3A4 inducers (e.g., phenytoin, rifampin).
• Uncontrolled hypertension or hypokalemia without correction.

• Hepatotoxicity: Monitor LFTs regularly; dose adjust or discontinue if elevations persist.
• Adrenocortical Insufficiency: May occur due to CYP17 inhibition; manage with corticosteroids.
• Hypertension, Hypokalemia, and Fluid Retention: Due to mineralocorticoid excess; monitor electrolytes and BP.
• Cardiovascular Risk: Use with caution in patients with underlying cardiovascular disease.
• Drug Handling: Tablets must be handled with care; avoid exposure to crushed tablets.

• Common (≥10%):
• Endocrine/Metabolic: Hypokalemia, hypertension, fluid retention.
• Hepatic: Elevated ALT/AST.
• GI: Diarrhea, dyspepsia.
• General: Fatigue, joint swelling/discomfort, cough.
• Serious/Rare:
• Severe hepatotoxicity
• Adrenal insufficiency
• Cardiac arrhythmias
• Sepsis (in advanced disease)
• Dose-Related Effects:
• Mineralocorticoid-related adverse effects increase with lack of concurrent steroid use.

• Major Interactions:
• CYP3A4 inducers (e.g., rifampin): ↓ Abiraterone levels — avoid.
• CYP2D6 substrates (e.g., metoprolol, codeine): Abiraterone inhibits CYP2D6 — monitor for toxicity.
• CYP1A2 substrates: May increase plasma concentrations.
• Food Interaction:
• High-fat meals significantly increase drug exposure — must be taken on an empty stomach.
• Alcohol:
• No direct interaction, but caution in patients with liver disease.
• Enzyme Systems:
• CYP17A1 (target)
• Inhibits CYP2D6, CYP2C8 (moderate).

• FDA Labeling Updates:
• Expanded indication for mCSPC in combination with prednisone.
• Emphasis on adrenocortical insufficiency monitoring.
• NCCN & ESMO Guidelines:
• Strong recommendation for abiraterone plus prednisone in both mCRPC and mCSPC.
• Preference for abiraterone over chemotherapy in chemo-naïve hormone-sensitive patients.
• Recent Clinical Data:
• STAMPEDE and LATITUDE trials confirm significant survival benefit in high-risk patients.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Excursions: Allowable between 15°C and 30°C (59°F to 86°F).
• Handling:
• Keep in original container; protect from moisture.
• Do not crush or split tablets.
• Women of childbearing potential should avoid handling broken tablets.