Zytiga
Zytiga
Generic Name
Zytiga
Mechanism
Zytiga (abiraterone acetate) is a selective, irreversible inhibitor of the enzyme cytochrome P450 17α-hydroxylase/c17,20‑lyase (CYP17).
• CYP17 inhibition ↓synthesis of androgens in the adrenal cortex, testes, and tumor tissue.
• Resulting decline in intratumoral and systemic testosterone → suppression of androgen‑driven prostate cancer growth.
• No direct effect on gonadotropin release; therefore combination with prednisone is required to counteract the compensatory rise in ACTH and adrenal cortisol production.
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Pharmacokinetics
| Parameter | Typical Value | Key Comment |
| Absorption | Rapid, oral bioavailability ≈ 20–30 % (food increases absorption). | Dose with a low‑fat meal. |
| Distribution | Large volume of distribution (Vd ≈ 480 L); high plasma protein binding (~99 %). | Extensive tissue penetration, including bone and adrenal glands. |
| Metabolism | Primarily oxidized by CYP3A4 to the active metabolite abiraterone. | Inhibitor of CYP3A4; caution with strong inhibitors/inducers (e.g., ketoconazole, rifampicin). |
| Elimination | Hepatic excretion >90 %; fecal; minimal renal clearance. | Reduced systemic clearance in hepatotoxicity. |
| Half‑life | 3–4 h (parent) but active metabolite has a half‑life of ~8 h; overall therapeutic effect persists >24 h. | Once‑daily dosing adequate. |
| Drug interactions |
• Strong CYP3A4 inducers decrease abiraterone levels.
• Strong CYP3A4 inhibitors raise levels → ↑hypotension, hypokalaemia. | Monitor electrolytes if interacting agents. |
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Indications
- Metastatic castration‑resistant prostate cancer (mCRPC) in combination with prednisone (5 mg twice daily).
- Palliative therapy to delay or avoid the need for cytotoxic agents.
- Approved for use post‑chemotherapy and in patients who are androgen‑sensitive but with disease progression.
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Contraindications
Contraindications
• Active hepatic disease or unexplained transaminitis.
• Hypokalaemia, hyperkalaemia, or electrolyte imbalance that cannot be corrected.
• Recent thromboembolic event within 30 days (risk of vascular toxicity).
• Significant cardiovascular disease (e.g., uncontrolled hypertension, CHF).
Warnings
• Hypertension & Hypokalaemia: Can appear within the first month.
• Fluid retention, edema; may worsen heart failure.
• Hypo‑ or hyper‑adrenalism secondary to increased ACTH → must monitor cortisol levels.
• Gastro‑intestinal perforation reported in patients on concurrent NSAIDs or corticosteroids (rare).
Precautions
• Concomitant use of strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or inducers (rifampin, carbamazepine).
• Pregnancy: teratogenic in animal studies; women of childbearing potential require effective contraception.
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Dosing
- Initial dose: 1000 mg orally once daily.
- Co‑therapy: Prednisone 5 mg orally twice daily (morning & bedtime).
- Administration timing: oral dose in the morning; prednisone split into two doses.
- Food: can be taken with or without food; food increases absorption slightly.
- Re-dosing: acceptable if missed dose within ≤6 h of scheduled time; otherwise restart the day’s dose.
*Dose changes may be required in patients with hepatic impairment:
• Mild (Child‑Pugh A): 800 mg QD.
• Moderate (Child‑Pugh B): 600 mg QD.
• Severe (CYP‑3A4 inhibitors used): 500 mg QD.*
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Adverse Effects
| Adverse Effect | Incidence | Clinical Notes |
| Fatigue | ↑30 % | Dose‑adjustment rarely needed. |
| Decreased appetite / nausea | ↑20 % | Antiemetics may help. |
| Hypokalaemia | ↑15–20 % | Monitor K⁺; replace with potassium sucrose–sulfate. |
| Hypertension | ↑10–15 % | Regular BP check; antihypertensives may be required. |
| Fluid retention/edema | ↑8 % | Consider diuretics; monitor weight. |
| Elevated liver enzymes (ALT, AST) | ≤5 % | Hold therapy if >5 × ULN; resume when <3 × ULN. |
| Abdominal pain / failure | Rare | Watch for GI perforation. |
| Cardiac events (tachyarrhythmias, HF) | Rare (≤2 %) | Evaluate cardiac risk before starting. |
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Monitoring
- Baseline & serial: TSH, cortisol, serum creatinine, BUN, electrolytes (K⁺, Na⁺, Cl⁻), liver function tests (ALT, AST, ALP, bilirubin).
- Blood pressure: ≥2 times per month; more often if poorly controlled.
- Weight & fluid status: monthly to detect edema.
- Bone turnover markers: optional (especially in patients on bone‑active agents).
- CT/MRI: at baseline and every 12 weeks to gauge disease progression.
- Serum testosterone: optional, monitor for adequacy of suppression.
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Clinical Pearls
1. Prednisone Rescue
• Zytiga cannot be used alone; prednisone mitigates the adrenal side‑effects of CYP17 blockade.
• ICU CEP: If patients develop hyponatremia or hypokalaemia, first adjust pred dose before considering drug withdrawal.
2. Food–Absorption Strategy
• Taking abiraterone with a low‑fat meal improves absorption; skip high‑fat meals on the day of dosing to avoid erratic plasma peaks.
3. Drug Interaction “Check‑List”
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) double abiraterone exposure → raise cardiovascular risk.
• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine) halve exposure → therapeutic failure.
4. Liver‑Safety Protocol
• Discontinue Zytiga if ALT/AST >5 × ULN or if bilirubin rises >3 × ULN.
• Resumption requires both ALT/AST <3 × ULN and bilirubin <1.5 × ULN.
5. Elderly & Hepatic Impairs
• Start at half dose (500 mg) and titrate upward after 2–4 weeks if no toxicity and hepatic function normalizes.
6. Patient Education Focus
• Instruct patients to report new headaches, blurred vision, or leg swelling immediately.
• Teach self‑monitoring of blood pressure at home every 2–3 days during the first 2 months.
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• *This drug card merges critical pharmacological data with evidence‑based practice tips, offering a clear, searchable reference for clinicians treating castration‑resistant prostate cancer.*