Afinitor
Afinitor
Generic Name
Afinitor
Mechanism
- mTOR Inhibition: Afinitor binds FKBP‑12 → inhibits mTOR complex‑1 (mTORC1) and mTORC2, disrupting downstream signaling involved in cell growth, proliferation, and angiogenesis.
- Effects on the Cell Cycle: Induces G1‑phase arrest by down‑regulating Cyclin D1 and up‑regulating PTEN.
- Impact on Tumor Microenvironment: Suppresses VEGF‑A production, reducing angiogenesis and tumor vascular supply.
Pharmacokinetics
| Parameter | Typical Value | Notes |
| Absorption | 95 % by mouth; peak 1–2 h (high‑fat meals ↑ peak 1.5‑2 h) | Oral bioavailability high; food increases absorption. |
| Distribution | Vol. Distrib. ≈ 1.2 L/kg (high plasma protein binding 89‑95 %) | Tissue penetration adequate (e.g., CNS). |
| Metabolism | Primarily CYP3A4‑mediated hepatic oxidation; also CYP2C19 | Drug–drug interactions with strong CYP3A4 inhibitors/inducers. |
| Elimination | 68 % biliary; 32 % renal | Half‑life ~30 h; steady‑state ≈ 14 days. |
| Special Populations | Adjust for hepatic impairment; no dose adjustment needed for mild–moderate renal impairment. | Severe hepatic impairment: avoid. |
Indications
- Advanced renal cell carcinoma (RCC) – first‑line therapy with or without interferon‑α.
- Metastatic hormone‑positive HER2‑negative breast cancer – often combined with endocrine therapy.
- Pancreatic neuroendocrine tumors (pNET) – as monotherapy or combination.
- Subependymal giant cell astrocytoma in tuberous sclerosis complex (pediatric).
- Approved pediatric use in specific CNS tumors with TSC.
Contraindications
Contraindications
• Known hypersensitivity to temsirolimus or any component.
• Severe hepatic impairment (Child‑Pugh C).
Warnings
• Pneumonitis – pulmonary infiltrates, dyspnea.
• Stomatitis / Oral ulcers – may preclude dosing.
• Impaired wound healing – avoid surgery up to 7 days prior/following therapy.
• Glycologic disturbance – hyperglycemia, hyperlipidemia → monitor and control.
• Infection risk – opportunistic infections; vigilance for sepsis.
• Torsades‑de‑pointes – due to QT prolongation in severe cases; monitor ECG in QT‑long patients.
Dosing
- Adults (with adequate hepatic/renal function): 10 mg orally once daily.
- Renal dysfunction (CrCl ≥ 50 mL/min): 10 mg daily.
- Severe hepatic impairment: Avoid.
- Pediatric (TSC): 2 mg/m² orally or IV, every 7 days (dose adjustable by weight).
- Administration tips: Take with food to enhance absorption; avoid high‑fat meals if risk of hyperlipidemia; consistent 24‑h interval.
- Ongoing assessment: Evaluate compliance and adherence; educate about potential GI upset.
Monitoring
| Parameter | Frequency | Rationale |
| CBC, CMP | Every 2–3 weeks (first 2 months) | Detect neutropenia, liver injury |
| Blood glucose | Every 2–4 weeks | Prevent steroid‑like hyperglycemia |
| Lipid panel | Every 4 weeks | Mitigate pancreatitis risk |
| Chest X‑ray / HRCT (if respiratory symptoms) | On suspicion of pneumonitis | Early detection |
| ECG | Baseline; repeat if QT‑prolonging therapy added | Capture arrhythmias |
| Patient diary | Daily | Record mucositis, fatigue, appetite changes |
Clinical Pearls
- Start low, stay low: In patients on chronic steroids or with baseline lymphopenia, consider a 5‑mg daily starter dose, titrating to 10 mg when tolerated.
- Food synergy: A high‑fat meal increases bioavailability; use this strategically in patients on lipid‑normalizing agents.
- Pneumonitis sentinel: Even mild cough or shortness of breath warrants immediate imaging; early intervention with prednisone may avert dose‑limiting toxicity.
- Infection prophylaxis: For high‑risk patients, consider prophylactic antivirals (eg, valacyclovir) and antifungals (fluconazole) during the first 3 months.
- Breast‑cancer synergy: Combine with aromatase inhibitors to exploit complementary anti‑angiogenic and hormonal blockade pathways; monitor for overlapping endocrine side effects.
- Pediatric dosing: Weight‑based dosing (2 mg/m² every 7 days) avoids over‑exposure; maintain a pediatric-specific monitoring bundle especially for TSC lesions.
- Drug‑drug interactions: Concomitant potent CYP3A4 inhibitors (ketoconazole, clarithromycin) can raise temsirolimus exposure; use dose reduction or alternative antibiotics.
> Bottom line – Afinitor provides a valuable mTOR‑blocking strategy in advanced malignancies but requires vigilant monitoring for metabolic, pulmonary, and infectious complications. Early recognition of adverse events and proactive dose adjustments improve tolerance and therapeutic success.