Koselugo
Koselugo
Generic Name
Koselugo
Mechanism
- Checkpoint blockade – Koselugo binds to the cytoplasmic domain of programmed death‑1 (PD‑1) on activated T‑cells.
- Prevention of ligand engagement – By blocking PD‑1 interaction with PD‑L1/PD‑L2, it restores T‑cell activation, proliferation, and cytokine release.
- Enhanced anti‑tumor immunity – The resulting immune surveillance leads to tumor‑cell apoptosis and eventual tumor regression.
*Key pharmacologic concept: immune‑checkpoint inhibition.*
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Pharmacokinetics
| Parameter | Typical Value (IV 200 mg q3 wks) |
| Absorption | Intravenous – 100 % bioavailability |
| Distribution | Volume of distribution: ~3 L/kg; penetrates lymphoid tissues |
| Protein binding | ~93 % (to IgG) |
| Metabolism | Mainly catabolism to peptides; minimal hepatic metabolism |
| Elimination | Linear CL ≈ 0.7 mL/kg/min; half‑life ~20 days |
| Special populations | No dose adjustment for mild‑moderate renal or hepatic impairment; caution in severe disease |
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Indications
- Metastatic cutaneous melanoma refractory to at least one prior systemic agent (e.g., BRAF/MEK inhibitor, ipilimumab, or chemotherapy).
- Can be used as monotherapy; combination with other ICIs (e.g., ipilimumab) not yet FDA‑approved.
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Contraindications
| Category | Details |
| Contraindications | Hypersensitivity to murine protein fragments or polysorbate 80 (if present in formulation); active, uncontrolled autoimmune disease (e.g., severe rheumatoid arthritis, systemic lupus erythematosus). |
| Warnings |
• Immune‑related adverse events (irAEs): colitis, pneumonitis, hepatitis, endocrinopathies, dermatologic reactions.
• Neurotoxicity: rare neurologic deficits (e.g., myasthenia gravis, Guillain‑Barre).
• Infusion reactions: anaphylaxis, anaphylactoid. |
| Precautions |
• Pre‑existing organ‑specific dysfunction (e.g., pre‑existing thyroid disease).
• Pregnancy: No adequate human data; potential teratogenicity.
• Interactions: None specific, but concurrent use of other immune‑modulators, biologics, or long‑acting steroids may affect efficacy or toxicities. |
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Dosing
- Dose: 200 mg IV infusion every 3 weeks (q3 wks).
- Infusion time: 60 min for first dose, 30 min for subsequent doses.
- Premedication: Antihistamine (diphenhydramine) and acetaminophen to reduce infusion reaction risk; steroids only if prior irAEs.
- Re‑dosing: Continue until disease progression, unacceptable toxicity, or patient withdrawal.
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Adverse Effects
| Category | Typical Incidence |
| Common (≥10 %) | Fatigue, rash, pruritus, diarrhea, nausea, hyponatremia, headache |
| Serious (≥1–5 %) | Colitis (≥5 %), pneumonitis (≥5 %), hepatitis (≥10 %), endocrinopathies (hypothyroidism 10–20 %), hypophysitis (rare), nephritis, severe infusion reactions |
| Rare (<1 %) | Severe cutaneous reactions (e.g., Stevens–Johnson syndrome), neurologic irAEs |
*Early recognition and prompt management (often high‑dose steroids or immune‑suppressants) are critical.*
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Monitoring
| Parameter | Frequency | Rationale |
| Baseline labs – CBC, CMP, liver & renal panels | Pre‑dose | Detect pre‑existing cytopenias or organ dysfunction |
| Toxicity surveillance (rash, diarrhea, fever, respiratory symptoms) | During every visit | Early irAE detection |
| Endocrine panels – TSH/T4, cortisol, ACTH, fasting glucose | Baseline, then every 3 wks | Detect thyroiditis, adrenalitis, diabetes |
| Imaging (CT/MRI) | Every 8 wks | Evaluate tumor response per RECIST 1.1 |
| Pulmonary function / Chest CT | If respiratory symptoms | Identify pneumonitis |
| Skin exam | Every visit | Monitor for vitiligo, lichenoid dermatitis |
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Clinical Pearls
1. Pre‑existing autoimmune disease – These patients may still benefit if the disease is controlled; close monitoring for flare is essential.
2. Steroid use – Low‑dose prednisone (≤10 mg/day) does not negate efficacy; high doses may blunt response.
3. Infusion duration – Shortening infusion time (<30 min) after the first dose is safe for most patients and improves outpatient flow.
4. Endocrine irAEs – Hypothyroidism may remain after discontinuation; replace with levothyroxine permanently.
5. Patient education – Emphasize reporting symptoms of diarrhea, cough, abdominal pain, and skin changes immediately.
6. Combination therapy – While not approved with ipilimumab for melanoma, emerging data suggest potential synergy; enroll in trials when eligible.
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