Xtandi
Xtandi
Generic Name
Xtandi
Mechanism
- Competitive antagonist of the AR: Enzalutamide binds to the ligand‑binding domain of the androgen receptor with ~10‑fold higher affinity than testosterone, preventing androgen-induced activation.
- Multiple blockade steps:
1. Inhibits AR nuclear translocation (prevents AR from entering the nucleus).
2. Blocks chromatin binding (disrupts AR‑DNA interaction).
3. Reduces AR‑mediated transcription of genes driving prostate cancer proliferation.
• Reduced cross‑resistance to earlier 5α‑reductase inhibitors and gonadotropin‑releasing hormone analogues.
Pharmacokinetics
| Parameter | Value | Comments |
| Absorption | Oral | Peak plasma conc. (~5–6 h). Food increases Cmax by ~30 % (no dose adjustment needed). |
| Distribution | Volume ~1 L/kg; plasma protein binding 91 % | Binds mainly to albumin, not to blood cells. |
| Metabolism | Hepatic via CYP2C8 (major), CYP3A4, CYP2B6 | M1 (ortho‑hydroxylated) is active; total activity ~0.5× parent. |
| Elimination | Mostly fecal (≈ 84 %); renal excretion ~15 % of parent. | Half‑life 5–7 days. Clearance ≈ 4–6 mL/min/1.73 m² (hepatic). |
| Drug interactions | Potent CYP2C8/3A4 inducer or inhibitor alters enzalutamide levels; avoid strong CYP3A4 inducers (e.g., rifampin) or inhibitors (e.g., ketoconazole). | Concomitant use with strong CYP3A4 inducers requires dose reduction or alternative therapy. |
Indications
- Metastatic castration‑resistant prostate cancer (mCRPC), following prior docetaxel or in chemo‑naïve patients (per NCCN 2023).
- Non‑metastatic castration‑resistant prostate cancer (nmCRPC) with a PSA doubling time ≤ 10 months (per FDA label, 2021).
Contraindications
- Contraindicated: pregnancy (category X – teratogenic); severe hepatic impairment (Child‑Pugh C).
- Warnings:
- Seizures: 2–5 % risk in patients with a history of seizures or on concomitant antiepileptics.
- QT prolongation: Minimal risk; avoid in patients on strong CYP3A4 inhibitors or QT‑prolonging drugs.
- Cognitive impairment: Enzalutamide may worsen confusion/short‑term memory loss in elderly/brain‑metastasis patients.
- Precautions: monitor for neurotoxicity; avoid sudden dose reduction that could precipitate seizures.
Dosing
- Standard dose: 160 mg orally once daily.
- Administration: Take with or without food; maintain consistent daily timing.
- Treatment duration: Continue until disease progression or unacceptable toxicity; consider androgen‑suppression therapy in combination regimens.
Adverse Effects
| Category | Typical Incidence | Management |
| Fatigue | 25–30 % | Dose hold, supportive care, exercise |
| HTN, edema | 10–15 % | Monitor BP, diuretics for edema |
| Seizure (rare) | 2–5 % | Discontinue in seizure‑prone patients; consider alternative AR blockade |
| Liver enzyme elevations | Mild in 5–10 % | Monitor LFTs; hold dose if ≥ grade 2 |
| Neurologic (confusion, dizziness) | 5–7 % | Dose delay/hold; avoid CNS‑penetrating drugs |
Serious but less common:
• Pulmonary embolism (≈ 0.5 %): Anticoagulate if high risk, monitor for dyspnea.
• Cardiac arrest (very rare, < 0.5 %): Immediate discontinuation for patients with arrhythmias.
Monitoring
- Baseline labs: CBC, CMP, PSA, liver enzymes, electrolytes.
- During therapy:
- PSA every 4–6 weeks (early response) then every 12 weeks.
- LFTs and renal function every 8 weeks initially, then at each clinic visit.
- Blood pressure and weight at every visit to detect fluid retention.
- Imaging: CT/MRI or bone scan at 12–16 weeks or per clinical judgment to assess radiographic progression.
- QTc interval: Baseline EKG; repeat if receiving QT‑prolonging agents.
Clinical Pearls
- Timing of dose: Taking the tablet at the same time daily reduces variability; a single‑dose “break” can still maintain steady‑state.
- Seizure risk mitigations: In patients on levetiracetam or phenytoin, consider initiating enzalutamide at a lower dose (80 mg) and titrating up if needed.
- Cognitive complaints: Evaluate for drug interactions (e.g., strong CYP3A4 inhibitors) and consider neuro‑cognitive testing if confusion arises early in therapy.
- Pregnancy testing: Mandatory before initiation and during therapy due to teratogenic potential; use reliable contraception.
- Drug–drug interaction pearls:
- Avoid strong CYP3A4 inhibitors (ketoconazole) – risk ↑ seizure, toxicity.
- Avoid strong CYP3A4 inducers (rifampin, St. John’s wort) – risk ↓ drug levels, sub‑therapeutic.
- Transition to chemotherapy or radiotherapy: No overlap needed; discontinue enzalutamide 4 weeks before high‑dose docetaxel or targeted radionuclide therapy due to overlapping neurotoxicity.
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• *This drug card synthesizes the most current evidence for clinical practice; always check institutional guidelines and the latest product labeling before use.*