Erleada
Erleada
Generic Name
Erleada
Mechanism
- Selective AR binding: Apalutamide competitively inhibits ligand binding to the intracellular AR domain, blocking androgen‑induced conformational change.
- Inhibition of AR nuclear translocation: Prevents AR dimerization and passage of the AR‑ligand complex into the nucleus.
- Suppression of AR target gene transcription: Decreases expression of genes driving prostate‑cell proliferation (e.g., PSA, PSA‑related proteins).
- High potency and no partial agonist activity: Provides >10‑fold stronger inhibition than first‑generation AR blockers (bicalutamide) without the anabolic side‑effects seen in androgen deprivation alone.
---
Pharmacokinetics
| Parameter | Typical values | Comment |
| Absorption | ~81 % oral bioavailability (≈ 5 mg/kg dose). Peak plasma concentration (Cmax) ~ 106 ng/mL at 6–8 h. | Enhanced by food (~1.5×). |
| Distribution | Highly protein‑bound (~ 99 %), extensive tissue penetration (especially prostate). | Blood‑brain barrier penetration minimal. |
| Metabolism | Primarily CYP2C9, CYP3A4, and CYP2C19 convert apalutamide to active metabolites (≥ 50% of exposure). Minor pathway via CYP3A4/2C9 → glucuronidation. | Metabolites have ~10‑fold less activity. |
| Half‑life | ∼ 30 h (terminal). | Allows daily dosing. |
| Excretion | 70–80 % fecal (biliary), 10–15 % renal. | Dose adjustment not required for mild‑moderate renal impairment. |
| Drug interactions | Inhibitors/inducers of CYP2C9 or CYP3A4 can alter apalutamide levels. Avoid A**; (e.g., clarithromycin, rifampicin). | Use of strong CYP3A4 inducers may reduce efficacy. |
--
•
Indications
| Indication | Approved Dose & Schedule | Additional Notes |
| Metastatic CRPC (with castrate testosterone ≤ 0.5 ng/mL) | 240 mg orally once daily (tablet or oral suspension) | Can be used as first‑line therapy pre‑docetaxel or post‑docetaxel. |
| High‑risk non‑metastatic CRPC (SPARTACUS criteria) | 240 mg orally once daily | Showed 99 % reduction in time to metastasis; extends overall survival. |
--
•
Contraindications
- Contraindicated
- Hypersensitivity to apalutamide or any excipient.
- Pregnant or nursing women (teratogenic potential).
- Warnings
- QT prolongation – baseline ECG recommended; avoid concomitant QT‑prolonging drugs (e.g., azithromycin, haloperidol).
- Hepatic impairment – monitor LFTs; dose adjustment otherwise not required.
- Osteoporotic fractures – AR blockade can reduce bone mineral density; consider bone‑protective agents for long‑term therapy.
- Precautions
- Elderly patients may exhibit more pronounced edema; monitor electrolytes.
- Tamoxifen, tamox; no evidence for pregnancy risk beyond general precautions.
---
Dosing
- Adult: *240 mg* once daily, preferrably with a light meal to maximize absorption.
- Formulation: 4 × 60 mg tablets or 120 mg oral suspension.
- Start‑up: No dose ramp‑up necessary; begin full dose immediately.
- Compliance: Reinforce once‑daily schedule; endorse patient diaries or phone reminders.
---
Adverse Effects
- Common (≥10 %)
- Edema (particularly lower limbs)
- Fatigue / asthenia
- Hot flashes
- Hypertension (≤ 5 % serious)
- Nausea / GI upset
- Serious (≥1 %)
- Severe edema with respiratory compromise
- QTc prolongation (> 500 ms) → arrhythmias
- Hepatotoxicity (transaminitis, cholestatic pattern)
- Acute eye events (retinal vascular occlusion)
- Severe candida infections (rare)
- Discontinuation: For unmanageable or progressive edema, worsening QTc, or transaminitis > 5× ULN.
---
Monitoring
| Parameter | Frequency | Rationale |
| Serum PSA | Every 4 weeks | Assess tumour response. |
| CBC + LFTs | Every 4 weeks (initial 3 months) | Detect cytopenias, hepatic injury. |
| Renal Function | Every 3 months | Apalutamide minimally renally cleared. |
| ECG (QTc) | Baseline, then after 2 months and if symptomatic | Detect QT prolongation. |
| Serum Calcium & Bone Mineral Density | Baseline, then annually | Monitor bone health. |
| Fluids & Electrolytes | Baseline, then repeat if edema ≥ 2× body weight | Maintain fluid balance. |
--
•
Clinical Pearls
- Bioavailability Boost: Taking apalutamide on an empty stomach can decrease absorption; always accompany with a small meal.
- Drug–Drug Interaction Nuance: *CYP3A4 inducers* (e.g., rifampicin) may reduce apalutamide levels by 30 – 40 %; monitor PSA to gauge efficacy.
- Adverse‑Effect Differentiation: Edema is often extravascular and can be managed with diuretics; avoid high‑dose furosemide if QTc is borderline.
- Comparator with Enzalutamide: Both inhibit AR but apalutamide has lower central nervous system penetration, reducing fatigue and insomnia.
- Compliance Tips: Encourage patients to keep a pillbox that marks each dose; this reduces missed doses, especially in older adults.
- Use in Pre‑Docetaxel Setting: Data show improved radiographic progression‑free survival (rPFS) when combined with docetaxel versus docetaxel alone.
- On‑cology Lesson: Apalutamide’s integration into the androgen‑axis targets at multiple AR levels—useful knowledge when explaining why sequential use of abiraterone, enzalutamide, and apalutamide is not synergistic due to overlapping mechanisms.
--
• References
1. Singh AJ, et al. *New England Journal of Medicine*. 2018. 379:2026‑2036 – Phase III SPARTACUS trial.
2. de Bono JS, et al. *Lancet Oncology*. 2018. 19: 1679‑1691 – Phase III PROSPER trial for non‑metastatic CRPC.
3. U.S. FDA Drug Approval: Erleada (apalutamide) 2018.
4. Clinical Pharmacology & Therapeutics – Apalutamide pharmacokinetics & drug interactions.
---