Zydelig
Zydelig
Generic Name
Zydelig
Mechanism
- Selective inhibition of the regulatory subunit p110δ of phosphoinositide 3‑kinase (PI3K), a key signal transducer in B‑cell receptor pathways.
- Blocks downstream Akt/mTOR signaling → ↓ B‑cell proliferation, migration, and survival.
- Induces apoptosis selectively in malignant B‑cells while sparing most normal cells, which express other PI3K isoforms.
Pharmacokinetics
| Parameter | Value / Note | ||
| Absorption | Oral; peak t ≈ 1–3 h; bioavailability ~50% (food increases absorption modestly). | ||
| Distribution | |||
| • Volume of distribution ≈ 1.8 L/kg | • Highly protein‑bound (~30 % free). | ||
| Metabolism | Primarily CYP3A4 oxidation (via CYP3A4/5). Minor CYP2C19 contribution. | ||
| Elimination | |||
| • Half‑life ≈ 10–16 h (steady‑state 14–16 h). | • 60 % excreted in feces, 40 % in urine (mostly conjugated metabolites). | ||
| Drug‑Drug Interactions | • Strong CYP3A4 inhibitors (ketoconazole, itraconazole) ↑ idelalisib → dose ↓ or avoid. | • Strong CYP3A4 inducers reduce exposure (rifampin). | • Avoid co‑administration with other immunosuppressants that risk colitis/infection. |
Indications
- Relapsed/refractory follicular lymphoma (with or without anti‑CD20 antibodies).
- Relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with at least one prior treatment.
- Relapsed marginal zone lymphoma in patients previously treated with anti‑CD20 therapy.
Contraindications
- Known hypersensitivity to idelalisib.
- Active gastrointestinal infection (e.g., C. difficile).
- Severe hepatic impairment (Child‑Pugh B/C).
- Active or latent tuberculosis, fungal, or viral infections that require immunosuppression.
- Cytopenias with absolute neutrophil count < 1 × 10⁹/L or platelet count < 50 × 10⁹/L.
- Concurrent treatment with drugs requiring potent CYP3A4 inhibition (unless dose is halved and monitored).
Warnings
• Colitis/diarrhea – immune‑mediated enterocolitis.
• Transaminase elevations – hepatotoxicity, requires monitoring.
• Pneumonitis / pulmonary toxicity – hypersensitivity pneumonitis/ALI.
• Inflammatory bowel disease flare – caution in patients with Crohn’s disease, ulcerative colitis.
Dosing
- Standard dose: 150 mg orally twice daily (BID), taken with food.
- Initial 28‑day “lead‑in”: 50 mg BID in combination regimens (e.g., with rituximab) – *only for clinical trials/expanded access*.
- Adjust for hepatic impairment: Use lower dose (e.g., 75 mg BID) only if clinically justified.
- Titration: No dose escalation; discontinue if grade ≥ 3 adverse events.
- Storage: 15–30 °C, protected from light.
Monitoring
| Parameter | Frequency | Rationale |
| CBC w/ diff | Every 2 weeks for first 3 months, then monthly | Detect neutropenia, thrombocytopenia |
| LFTs (AST, ALT, bilirubin) | Every 2 weeks front‑end, then every 4 weeks | Early hepatotoxicity detection |
| Renal function (creatinine) | Every 4 weeks | Though primarily hepatic clearance, drug accumulates in impaired renal function |
| Vital signs & weight | Routine visits | Monitor for systemic toxicity |
| GI symptoms | Patient‑reported at every visit | Identify early colitis |
| Pulmonary assessment | Symptom‑based; chest X‑ray if dyspnea | Detect pneumonitis |
• Discontinue idelalisib if ALT/AST > 3× ULN with symptoms or > 5× ULN without symptoms.
• Temporarily hold for Grade 2 colitis or transaminitis; resume at reduced dose only after resolution.
Clinical Pearls
- Idelalisib = PI3Kδ inhibitor → “B‑cell specific” profile, but not tumor‑specific; monitor for immune‑mediated toxicities.
- Use caution in patients with IBD: Pre‑existing Crohn’s/UC can flare; consider alternative therapy.
- Stop therapy immediately if severe colitis, hepatotoxicity, or pneumonitis develops; treat with high‑dose steroids (prednisone 1 mg/kg) before re‑initiation.
- Pre‑screen for TB and hepatitis B before initiating therapy due to immunosuppression risk.
- Drug‑interaction vigilance: Avoid co‑administration with strong CYP3A4 inhibitors; halve dose if unavoidable.
- Combination with rituximab is FDA‑approved for follicular lymphoma; however, synergy increases risk of colitis—use dose‑adjusted regimens in clinical trials, not standard care.
- Patient education: Emphasize prompt reporting of diarrhea, jaundice, or breathlessness.
- Discontinue if platelet count < 50 × 10⁹/L or ANC *Key take‑away*: While idelalisib offers durable remissions in otherwise refractory B‑cell lymphomas, vigilant monitoring for immune‑mediated adverse events and proactive dose adjustments are essential for safe, effective use.