Osimertinib
Osimertinib
Generic Name
Osimertinib
Mechanism
- Irreversible covalent binding to the cysteine‑797 residue of the EGFR ATP‑binding pocket → permanent inhibition of kinase activity.
- Selectively inhibits activating mutations (exon 19 deletions, L858R) and the resistance mutation T790M, while maintaining minimal inhibition of wild‑type EGFR.
- Down‑regulation of downstream signaling pathways (PI3K/AKT, RAS/RAF/MEK) → apoptosis and reduced proliferation of tumor cells.
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Pharmacokinetics
| Parameter | Details |
| Absorption | Oral bioavailability ~80 %; peak plasma conc. at 1–6 h; food increases exposure modestly (~30 %). |
| Distribution | Highly protein‑bound (~91 % to albumin), moderate CNS penetration (≈16 % of plasma). |
| Metabolism | Primarily CYP3A4/5‑mediated; minor CYP1A2, CYP2D6 contributions. |
| Elimination | Half‑life ~48 h; 50 % renal excretion, 30 % fecal, 20 % biliary; minimal impact of mild renal dysfunction. |
| Drug Interactions | Inducers of CYP3A4 (e.g., rifampin) reduce exposure; inhibitors (ketoconazole, grapefruit juice) increase plasma levels. |
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Indications
- First‑line therapy of metastatic NSCLC with EGFR exon 19 deletion or L858R mutation.
- Second‑line therapy after progression on first‑ or second‑generation EGFR TKIs if a T790M mutation is present (via tissue or liquid biopsy).
- Treatment of CNS metastases: evidence of superior intracranial activity due to blood–brain barrier penetration.
- Investigational use in other EGFR‑driven malignancies (e.g., triple‑negative breast cancer, colorectal cancer).
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Contraindications
| Category | Considerations |
| Contraindications | Hypersensitivity to osimertinib or any excipient. |
| Warnings | |
| • QT prolongation | Baseline ECG required; avoid concomitant QT‑prolonging agents. |
| • Hepatotoxicity | Monitor LFTs; hold drug if AST/ALT >8 × ULN. |
| • Interstitial lung disease (ILD) | High‑risk patients necessitate serial pulmonary exams. |
| • Pregnancy & Lactation | Category B; fetotoxic potential—use contraception. |
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Dosing
| Setting | Dose | Route | Schedule | Modifications |
| First‑line & T790M‑positive | 80 mg | Oral | Once daily | No dose adjustment for mild/moderate hepatic impairment; 40 mg for severe hepatic dysfunction. |
| Brain metastases | 80 mg | Oral | Once daily | Continue full dose; no need for CNS‑specific dosing. |
| Renal impairment | 80 mg | Oral | Once daily | No dose adjustment for CKD stages 1–3; careful monitoring. |
| Same‑day dosing | Take at same time each day; may be with or without food. |
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Adverse Effects
| Category | Adverse Effects |
| Common (≤30 %) |
• Rash (grade 1–2) • Diarrhea (grade 1–2) • Dry skin, paronychia • Stomatitis/mucositis • Alopecia • Fatigue • Hyponatremia |
| Serious (≥<1 %) |
• Interstitial lung disease (ILD) • B‑cell lymphoma / other hematologic toxicity • QTc prolongation >500 ms • Severe rash (grade 3–4) • Hepatotoxicity (AST/ALT >8 × ULN) • Cardiomyopathy/borderline heart failure |
*Management:* symptomatic treatment for rash/diarrhea, dose interruption for ILD or hepatotoxicity, cardiology referral for QTc prolongation.
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Monitoring
| Parameter | Timing | Rationale |
| Baseline ECG | Pre‑treatment | Detect pre‑existing QTc prolongation |
| Serial ECG | Every 4–6 weeks | Monitor QTc changes |
| Liver Function Tests (LFTs) | Baseline & every 4 weeks | Early detection of hepatotoxicity |
| CBC with differential | Baseline & every 4 weeks | Monitor for hematologic toxicity |
| Electrolytes (Na, K, Mg, Ca) | Baseline & every 4 weeks | Aldronic acid changes, hyponatremia |
| Pulmonary evaluation (PFTs, chest imaging) | Baseline + as clinically indicated | ILD risk assessment |
| Body Weight & BMI | Every visit | Appetite changes, cachexia |
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Clinical Pearls
- Early Skin Care: Initiate topical corticosteroid ointments and moisturizers at the start of therapy; promptly treat grade 2+ rash to avoid dose interruptions.
- Diarrhea Prevention: Prophylactic loperamide (1 mg at onset of loose stool, then 0.5–1 mg/d) can reduce treatment‑interruption risk.
- Drug Interaction Vigilance: Strong CYP3A4 inducers (rifampin, carbamazepine) can markedly lower osimertinib levels—consider alternative agents or adjust dose.
- CNS Mastery: Because osimertinib penetrates the CNS, it is the preferred agent for first‑line treatment of patients with asymptomatic brain metastases. Use serial MRI to detect progression early.
- Resistance Patterns: Upon progression, consider re‑biopsy for MET amplification or HER2 over‑expression – switching to MET‑targeted therapy or combination regimens may be beneficial.
- Pregnancy Counseling: Stop osimertinib at the earliest sign of pregnancy; the drug is teratogenic in animal studies.
- Pediatric Use: Limited data in children; no established dosing, but caution advised.
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• Key Takeaway:
Osimertinib offers durable control of EGFR‑mutant NSCLC, especially in patients with T790M resistance or CNS involvement. Its concise dosing schedule and specific safety monitoring enable clinicians to tailor therapy effectively while mitigating adverse events.