Generic Name

Enzalutamide

Mechanism

• Enzalutamide is a second‑generation, non‑steroidal antagonist that binds with high affinity to the ligand‑binding domain of the androgen receptor (AR).
• It blocks AR nuclear translocation, DNA binding, and recruitment of co‑activators, preventing transcription of AR‑dependent genes.
• Additionally, it suppresses intratumoral androgen synthesis and obstructs AR enhancer elements in prostate cancer cells.

Pharmacokinetics

• Absorption – oral bioavailability ≈ 86%; peak plasma concentration reached 6–12 h after dosing.
• Distribution – volume of distribution ~107 L; protein binding ~70 % (primarily albumin); limited CNS penetration; crosses the placenta.
• Metabolism – mainly hepatic via CYP2C8 and CYP3A4; primary inactive metabolites are N‑desmethyl and N‑toluyl.
• Elimination – 80 % renal, 20 % biliary; elimination half‑life 5–6 days (steady‑state ~6 weeks).
• Drug interactions – potent CYP3A4 inducer and inhibitor; avoid co‑administration with strong CYP3A4 inducers (e.g., rifampin) and inhibitors (e.g., ketoconazole).

Indications

• Metastatic castration‑resistant prostate cancer (mCRPC) in patients receiving docetaxel or those unsuitable for chemotherapy.
• Metastatic hormone‑naïve prostate cancer (mHNPC) as adjuvant therapy to androgen‑deprivation therapy (ADT) in high‑risk disease to improve overall survival.

Contraindications

• Contraindications – hypersensitivity to Enzalutamide or its excipients; concomitant strong CYP3A4 inducers.
• Warnings
• Seizures: 4–5 % incidence; risk increases with CNS disorders or illicit drug use.
• Pregnancy: teratogenic; contraindicated in women who may become pregnant; require barrier contraception.
• Hepatic impairment: avoid in severe (Child‑Pugh C) liver disease.
• QT prolongation: minimal effect, but monitor in patients on other QT‑prolonging drugs.

Dosing

• Standard adult dose – 160 mg orally once daily, taken with food.
• Optional titration – 80 mg daily for 4 weeks, then 160 mg to mitigate neurotoxicity.
• No dose adjustment for renal impairment; reduce to 80 mg in Child‑Pugh B hepatic dysfunction.

Adverse Effects

• Common (≥ 10 %) – fatigue, hot flashes, hypertension (≈ 6 %), nausea, mild dizziness.
• Serious – seizures (1–2 %), hypotension, deep venous thrombosis/pulmonary embolism, transaminase elevations.

Monitoring

• Baseline: CBC, CMP, PSA, alkaline phosphatase.
• Labs every 3–4 weeks during first 3 months, then every 6 weeks.
• Blood pressure – daily initially; treat per standard protocols.
• Liver function – bi‑weekly first 2 months; adjust if AST/ALT > 3 × ULN.
• Review for seizure risk and CNS history at dose changes.
• QTc – monitor if combined with other QT‑prolonging agents.

Clinical Pearls

• Titration Strategy: Beginning with 80 mg for 4 weeks reduces seizure risk by ~30 % without compromising efficacy.
• Drug‑Drug Interaction: Enzalutamide induces CYP3A4, shortening the half‑life of ketoconazole, itraconazole, and propranolol—consider dose adjustment or alternatives.
• Combination with Docetaxel: Maintain 160 mg dosing when given with docetaxel; avoid the 80‑mg regimen during chemotherapy.
• Bone Health: All mCRPC patients benefit from bisphosphonates or denosumab; routine bone‑density monitoring mitigates fracture risk.
• Patient Counseling: Stress the importance of daily adherence; a missed dose >12 h can lead to subtherapeutic AR blockade—prompt physician contact is essential.