Zytiga - Drug Monograph

Introduction

Zytiga (abiraterone acetate) is an oral androgen biosynthesis inhibitor used in the management of metastatic castration-resistant prostate cancer (mCRPC) and, in selected settings, metastatic high-risk castration-sensitive prostate cancer (mCSPC). It selectively blocks cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), reducing androgen production in the testes, adrenal glands, and within the tumor itself. Its clinical relevance lies in providing a targeted endocrine option that improves overall survival in advanced prostate cancer when combined with prednisone and appropriate androgen-deprivation therapy.

Drug Class and Overview

• Drug class: Androgen biosynthesis inhibitor; 17α-hydroxylase/17,20-lyase (CYP17) inhibitor; oral antiandrogen (second-generation hormonal agent).
• Related agents: Ketoconazole (a less selective, weaker inhibitor historically used off-label); enzalutamide, apalutamide, and darolutamide (androgen-receptor antagonists, distinct mechanism).
• Distinguishing features:
• Blocks androgen synthesis upstream (CYP17), depleting both testicular and adrenal androgens and intratumoral androgen production.
• Must be given with prednisone to mitigate mineralocorticoid excess (hypertension, hypokalemia, fluid retention).
• Given on an empty stomach (food markedly increases exposure).
• Available as conventional 250 mg tablets and a fine-particle 500 mg tablet formulation with different food effect profiles.

Mechanism of Action

Abiraterone acetate is a prodrug that is hydrolyzed in vivo to abiraterone, which selectively and irreversibly inhibits CYP17 (17α-hydroxylase/C17,20-lyase). CYP17 catalyzes two key steps in androgen biosynthesis: the conversion of pregnenolone and progesterone to their 17α-hydroxy intermediates, and the subsequent conversion of 17α-hydroxypregnenolone to dehydroepiandrosterone (DHEA) and of 17α-hydroxyprogesterone to androstenedione. Inhibition reduces circulating testosterone to castrate levels (<50 ng/dL) even when gonadal production is suppressed, and decreases intratumoral androgens. Because CYP17 inhibition also leads to accumulation of mineralocorticoid precursors, exogenous glucocorticoid (prednisone) replacement is required to suppress ACTH-driven precursor buildup and to treat potential adrenal insufficiency.

Indications

• Metastatic castration-resistant prostate cancer (mCRPC), in combination with prednisone:
• In patients who have received prior chemotherapy (docetaxel).
• In patients who are chemotherapy-naive (asymptomatic or mildly symptomatic).
• Metastatic high-risk castration-sensitive prostate cancer (mCSPC), in combination with prednisone and androgen-deprivation therapy.
• (Note: use is generally restricted to male patients; efficacy in female patients is not established.)

Dosage and Administration

• mCRPC and mCSPC (conventional 250 mg tablets): 1000 mg orally once daily (four × 250 mg tablets) on an empty stomach.
• Fine-particle 500 mg tablet: 500 mg orally once daily, with or without food (per formulation-specific labeling). Doses of the two formulations are not interchangeable on a mg-per-mg basis without considering food effect differences.
• Co-administration: Must be given with prednisone 5 mg orally twice daily (typical in mCRPC) or 5 mg once daily (commonly used in mCSPC); gonadotropin-releasing hormone agonist/antagonist should be continued in patients who have not undergone orchiectomy.
• Hepatic impairment:
• Mild (Child-Pugh A): no initial adjustment; monitor closely.
• Moderate (Child-Pugh B): reduce dose (commonly to 250 mg once daily for the conventional tablet) per labeling guidance; if hepatotoxicity occurs, withhold and adjust.
• Severe (Child-Pugh C): avoid use (not recommended).
• Renal impairment: No specific dose adjustment required for mild-to-moderate renal impairment; use with caution in severe renal impairment, as experience is limited.
• Pediatric: Not indicated; safety and efficacy not established.
• Geriatric: No unique dose adjustment; monitor for cardiovascular and hepatic adverse effects.
• Pregnancy: Not indicated in females; contraindicated in pregnant women (theoretical risk of fetal harm due to androgen blockade). Women of reproductive potential should not handle crushed/broken tablets.

Pharmacokinetics

• Absorption: Abiraterone acetate is rapidly converted to abiraterone; time to peak plasma concentration ~2 hours. The conventional tablet must be taken on an empty stomach because food (especially high-fat meals) increases exposure (AUC) several-fold. The fine-particle formulation has different absorption characteristics and is taken without regard to meals per its specific label.
• Distribution: Highly protein-bound (~99%) to albumin and α1-acid glycoprotein; large apparent volume of distribution.
• Metabolism: Abiraterone is metabolized in the liver, primarily via CYP3A4 and to a lesser extent by sulfation (SULT2A1). Active metabolites include abiraterone N-oxide sulfate and others of uncertain clinical activity.
• Elimination: Primarily fecal (~88%, mostly as metabolites) with minor renal excretion (~5%); half-life of abiraterone in plasma is approximately 12–24 hours (steady state achieved within ~2 weeks of daily dosing).
• Pharmacokinetic notes: Exposure is increased in hepatic impairment; avoid strong CYP3A4 inhibitors/inducers when possible, or monitor carefully.

Contraindications

• Pregnant women (or women who may become pregnant) — risk of fetal harm.
• Patients with known hypersensitivity to abiraterone acetate or any component of the formulation.
• (Severe hepatic impairment is a labeled "not recommended" condition rather than a strict contraindication; refer to labeling.)

Warnings and Precautions

• Hepatotoxicity: Increases in serum transaminases (ALT/AST) and rare cases of fulminant hepatitis and acute hepatic failure have been reported. Monitor liver function tests (LFTs) before starting, every 2 weeks for the first 3 months, then monthly. Withhold or discontinue for significant elevations (commonly defined per labeling at ≥5× upper limit of normal or symptomatic hepatotoxicity) and restart cautiously when values normalize.
• Mineralocorticoid-related effects: Hypertension, hypokalemia, and fluid retention/edema due to CYP17 blockade. Prednisone co-administration mitigates this; monitor blood pressure, serum potassium, and signs of fluid overload, especially in patients with cardiovascular disease.
• Cardiovascular disease: Use with caution in patients with recent myocardial infarction, uncontrolled hypertension, heart failure, arrhythmias, or other significant cardiac conditions; safety in NYHA Class III–IV heart failure is limited.
• Adrenocortical insufficiency: Can occur if prednisone is interrupted or during periods of stress (infection, surgery, trauma); patients should receive stress-dose corticosteroids as appropriate.
• Increased glucocorticoid requirements under stress: Educate patients and clinicians about sick-day rules.
• Bone density and fracture risk: Long-term androgen suppression may reduce bone mineral density; consider monitoring and supplementation (calcium/vitamin D) as indicated.

Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir): May increase abiraterone exposure; if unavoidable, monitor for toxicity and consider holding or dose adjustment per labeling.
• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort): May decrease abiraterone exposure and efficacy; avoid concomitant use when possible.
• CYP2D6 substrates with narrow therapeutic index (e.g., thioridazine, certain antidepressants/antipsychotics): Abiraterone may inhibit CYP2D6 and raise exposure to such agents; use caution and consider dose adjustment of the substrate.
• Spironolactone: May bind androgen receptor and confound prostate-specific antigen (PSA) interpretation; generally avoided.
• Live vaccines: Concurrent immunosuppression from prednisone warrants caution.
• Food interactions: Conventional tablets must be taken on an empty stomach; high-fat meals can dramatically increase exposure.

Adverse Effects

Common (general frequency language):

• Fatigue
• Arthralgia
• Hypertension
• Peripheral edema
• Hot flush
• Diarrhea
• Nausea
• Hypokalemia
• Mild transaminase elevations

Serious/less common:

• Severe hepatotoxicity (rare fulminant hepatic failure)
• Symptomatic heart failure, cardiac arrhythmias, ischemic events
• Adrenal insufficiency
• Severe hypokalemia
• Allergic reactions
• Increased fracture risk with long-term use

(Exact incidence depends on the trial population and whether prednisone dose is 5 mg vs 10 mg; specific percentages vary across sources.)

Monitoring Parameters

• Liver function tests (ALT, AST, bilirubin): Baseline, every 2 weeks for the first 3 months, then monthly.
• Blood pressure and signs of fluid retention: Baseline and regularly (at least monthly), with more frequent checks in patients with hypertension or cardiovascular disease.
• Serum potassium: Baseline and periodically, especially if on diuretics or with a history of hypokalemia.
• Adrenal insufficiency symptoms: During illness, trauma, surgery, or with prednisone interruption.
• PSA and clinical/disease response: Per oncology follow-up schedule; rising PSA may indicate disease progression.
• Renal function and electrolytes: Periodically, particularly in patients on diuretics or with comorbidities.
• Bone health: Calcium, vitamin D, and bone density in patients on prolonged therapy.

Patient Education

• Take abiraterone exactly as prescribed; do not change the dose or stop prednisone without talking to your clinician.
• Take the conventional 250 mg tablets on an empty stomach: no food for at least 2 hours before and 1 hour after the dose. The 500 mg fine-particle formulation has different instructions — follow the label exactly.
• Swallow tablets whole; do not crush, chew, or break them (women who are or may become pregnant should not handle broken tablets).
• Report yellowing of skin/eyes, dark urine, severe nausea/vomiting, right-sided abdominal pain, unusual fatigue, dizziness, fainting, palpitations, severe headache, marked swelling, or muscle weakness to your clinician.
• Take prednisone with food as directed; do not stop prednisone suddenly.
• Use caution with new medications (including over-the-counter and herbal products) — call your pharmacist/clinician before starting anything new.
• Maintain blood pressure monitoring at home if recommended; keep follow-up lab appointments.
• Pregnant women should not handle crushed or broken tablets; effective contraception should be used as appropriate for the patient and partner.
• During illness, injury, or surgery, tell the treating clinician you are on abiraterone and prednisone (stress-dose steroid may be required).

Clinical Pearls

• Always co-prescribe prednisone — omitting it risks mineralocorticoid excess (hypertension, hypokalemia, fluid overload) and adrenal insufficiency.
• The conventional 250 mg tablet formulation must be taken fasting; the 500 mg fine-particle tablet is taken with or without food. Do not substitute or extrapolate doses between formulations without checking the specific prescribing information.
• Hepatotoxicity is the dose-limiting toxicity in practice; aggressive LFT monitoring (every 2 weeks × 3 months) catches most clinically significant transaminase elevations early.
• Abiraterone acts upstream of the androgen receptor, distinguishing it from enzalutamide and other AR antagonists; combining with AR antagonists has been studied and is generally not recommended outside clinical trials due to overlapping toxicity and unclear benefit.
• Watch for drug–drug interactions via CYP3A4; counsel patients to avoid grapefruit and to disclose all concomitant medications, including herbals like St. John's wort.
• In patients undergoing surgery or significant physiologic stress, anticipate adrenal insufficiency and consider stress-dose corticosteroids in coordination with anesthesia/primary teams.

References

1. Janssen Biotech / Centocor Ortho Biotech. Zytiga (abiraterone acetate) Prescribing Information. U.S. Food and Drug Administration. (Latest FDA-approved label.)
2. European Medicines Agency. Zytiga (abiraterone acetate) Summary of Product Characteristics (SmPC).
3. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. New England Journal of Medicine (2011).
4. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. New England Journal of Medicine (2013).
5. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. New England Journal of Medicine (2017).
6. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Prostate Cancer (current version).
7. American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) guidelines for castration-resistant and advanced prostate cancer (current version).
8. Brunton LL, Knollmann BC (eds). Goodman & Gilman's The Pharmacological Basis of Therapeutics (edition current at time of writing).
9. Katzung BG, Vanderah TW (eds). Basic & Clinical Pharmacology (edition current at time of writing).
10. Lexicomp Online. Abiraterone Acetate: Drug Information (clinical reference database).
11. U.S. Food and Drug Administration. FDA approves abiraterone acetate (Zytiga) for metastatic castration-sensitive prostate cancer (labeling history).
12. World Health Organization (WHO) Essential Medicines List — entry for abiraterone (current listing).