Generic Name

Abiraterone

Mechanism

• Inhibition of CYP17: Blocks 17α‑hydroxylase and 17,20‑lyase activities, halting production of androgens (testosterone, dihydrotestosterone) in the testes, adrenal glands, and prostate tumor tissue.
• Reduction of Androgenic Stimulation: Lowers serum testosterone to <50 ng/dL, suppressing androgen‑dependent tumor growth.
• Bile Acid Pathway Suppression: Decreases corticosterone and mineralocorticoid precursors, leading to compensatory increase in cortisol (necessitates steroid supplementation to prevent adrenal insufficiency).

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Pharmacokinetics

• Formulation: Oral tablets; lipophilic compound.
• Absorption: Peak plasma concentrations at ~1–3 h post‑dose; absolute bioavailability ~30 % but increases 4‑fold when taken with food (high‑fat meal).
• Distribution: Extensive plasma protein binding (>90 %); highly lipophilic, tissue distribution including adrenal cortex and prostate.
• Metabolism: Primarily hepatic via CYP3A4, with several metabolites; metabolite of note – D4A (an active metabolite forming after deacetylation).
• Elimination: Dual excretion pathways: ~50 % renal; remainder fecal (via biliary excretion). Metabolite shedding extends half‑life (~2–3 days active drug).

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Indications

• Metastatic castration‑resistant prostate cancer (mCRPC) *in combination* with low‑dose prednisone or hydrocortisone.
• Neoadjuvant/adjuvant setting: In high‑risk localized prostate cancer (≥T3/≥N1 or Gleason ≥8) *with androgen deprivation therapy* (ADT).
• Earlier stage prostate cancers: Phase‑III trials (LATITUDE, STAMPEDE) support use of abiraterone with ADT in newly diagnosed high‑risk disease.

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Contraindications

• Contraindications:
• Severe hepatic disease (AST/ALT >3× ULN).
• Hypersensitivity to abiraterone acetate or excipients.
• Warnings:
• Fluid retention & hypertension due to mineralocorticoid excess.
• Heart failure exacerbation (use with caution).
• Adrenal insufficiency—requires co‑administration of corticosteroid (prednisone 5 mg BID, or hydrocortisone 12.5 mg QID).
• Pregnancy – category X; avoid use in pregnant or lactating women.
• Kidney impairment – dose adjustment not required but monitor renal function.

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Dosing

• Standard dose: 1 000 mg oral tablet once daily in the morning, fasting or with food (high‑fat meal optimizes absorption).
• Steroid companion: Prednisone 5 mg orally twice daily *or* hydrocortisone 12.5 mg orally four times daily.
• Post‑treatment: Continue prednisone for 3–6 months after discontinuation to mitigate adrenal failure risk.
• Switching to/from other ADT: No special washout period; use contraception if switching to an estrogen derivative (e.g., enzalutamide).

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Adverse Effects

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Monitoring

• Baseline: CBC, CMP (especially AST/ALT, creatinine), electrolytes (K+, Na+), BP, cardiac history.
• Periodic:
• Every 2–4 weeks: CBC, CMP, serum electrolytes, PSA (if applicable).
• Every 3 months (or sooner if clinical signs): assessment for fluid retention, hypertension, hepatic impairment.
• During Steroid Bridge: Monitor for adrenal suppression signs—night sweats, malaise, hypoglycemia.

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Clinical Pearls

• Food Interaction: A high‑fat breakfast markedly improves bioavailability (~4×); recommend patients take abiraterone immediately after (or with) their first substantial meal each day.
• Steroid Dosing: Prednisone 5 mg BID is the preferred schedule; it simplifies administration and reduces the risk of adrenal rebound. Hydrocortisone offers alternatives for patients intolerant to prednisone’s GI effects.
• CYP3A4 Inhibitors/Inducers: Strong inhibitors (e.g., ketoconazole) raise abiraterone plasma levels; inducers (e.g., rifampin) may lower therapeutic exposure—adjust dose or avoid co‑administration.
• Adrenal Surge in Chemotherapy: When abiraterone is added during chemotherapy for mCRPC, consider lengthening steroid cover to 6–12 months post‑treatment to prevent adrenal crisis.
• Fluid Retention Management: Initiate low‑dose spironolactone (25 mg twice daily) or amiloride to counteract mineralocorticoid excess before hypertension becomes clinically overt.
• Patient Selection: High‑risk localized prostate cancer patients (T3, N1, Gleason ≥8) benefit from adding abiraterone to ADT in the neoadjuvant/adjuvant setting—improves event‑free survival and overall survival.
• Renal Function: No dose adjustment necessary, but monitor serum creatinine; cystatin‑C may be more reliable in advanced cancer due to muscle wasting.

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• Key Takeaway: *Abiraterone* provides potent, systemic androgen blockade by inhibiting CYP17, but its clinical utility hinges on vigilant steroid co‑administration, monitoring for fluid overload, and careful patient selection in both metastatic and high‑risk localized prostate cancer settings.