Rapamune
Rapamune
Generic Name
Rapamune
Mechanism
- mTORC1 inhibition: Sirolimus binds to FKBP‑12 forming a complex that directly inhibits the mTOR complex‑1 (mTORC1) kinase.
- Blockade of G1‑S cell cycle progression: Inhibition of mTORC1 prevents phosphorylation of 4E‑BP1 and S6K1, which are essential for T‑cell activation and proliferation.
- Selective T‑cell suppression: B‑cell signaling is largely preserved; thus sirolimus reduces the risk of calcineurin inhibitor‑associated neurotoxicity and nephrotoxicity.
- Dual action on graft vs. host disease (GVHD): Its suppression of both T‑cell expansion and dendritic‑cell maturation dampens the alloreactive immune response in transplant and leukemia contexts.
Pharmacokinetics
| Feature | Details | |
| Absorption | Oral bioavailability ≈ 30–40 % (variable). Food increases AUC by ~12 %. | |
| Distribution | Volume of distribution ~ 372 L. Highly protein‑bound (~ 94 %). Crosses placenta; excreted in milk. | |
| Metabolism | Hepatic CYP3A4 and CYP3A5 metabolized to inactive oxidized metabolites. Minor UGT1A9 glucuronidation. | |
| Elimination | Primarily fecal (≈ 70 %) via biliary excretion. Renal clearance 40 mL/min); > 100 h in kidney < 30 mL/min. | |
| Drug‑Drug Interactions | Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, itraconazole, ritonavir) ↑ trough levels; CYP3A4 inducers (rifampin, carbamazepine) ↓ levels. | |
| Monitoring | Trough concentration target 3–15 ng/mL depending on indication; level peaks 2–4 weeks after loading dose. |
Indications
- Solid organ transplantation:
- Kidney transplant: maintenance in patients > 1 month post‑transplant, particularly when calcineurin inhibitor–associated nephrotoxicity is a concern.
- Liver transplant: maintaining immunosuppression; initial loading dose of 150 mg followed by daily dosing.
- Heart and lung transplant: maintenance therapy, usually combined with low‑dose calcineurin inhibitors.
- B‑cell malignancies (e.g., low‑grade follicular lymphoma, mantle‑cell lymphoma) in combination with rituximab.
- Prevention of biopsy‑proven acute rejection in childhood transplantation.
- Treatment of drug‑refractory chronic GVHD post‑bone‑marrow transplantation (off‑label but well‑established).
Contraindications
- Active infections (especially TB, fungal, viral hepatitis) – risk of severe infection.
- Severe hepatic or renal impairment (CrCl < 10 mL/min).
- Hypersensitivity to sirolimus or any component of the formulation.
- Pregnancy – category D; contraindicated due to teratogenicity (placenta‑crossing).
- Concurrent use of potent CYP3A4 inhibitors (e.g., ketoconazole) or major CYP3A4 inducers (e.g., rifampin) without dose adjustment.
- Concurrent antineoplastic agents that are strong CYP3A4 inhibitors (e.g., imatinib) may cause toxicity.
Warnings:
• Hematologic toxicity (anemia, leukopenia).
• Hepatotoxicity – transaminases up to 5× ULN; monitor LFTs.
• Hyperlipidemia – elevate triglycerides and cholesterol; start statins if needed.
• Wound healing impairment – relevant post‑surgical patients.
• Susceptibility to opportunistic infections (CMV, fungal, bacterial).
Dosing
| Indication | Initial Dose | Maintenance | Adjustment Notes |
| Kidney transplant | 10–15 mg orally once daily | Trough 5–10 ng/mL | Taper to 5 mg as trough stabilizes (> 6 months). |
| Liver transplant | 150 mg loading dose, then 5–10 mg daily | Trough 5–15 ng/mL | Loading dose to achieve therapeutic levels quickly. |
| Heart, lung | 1 mg/kg initial, then 5–8 mg daily | Trough 5–10 ng/mL | Lower dose in renal impairment. |
| GVHD | 4 mg/kg (modified for weight); typically 3–6 mg daily | Trough 5–10 ng/mL | Dose ↑ if disease uncontrolled. |
• Route: Oral capsules (3 mg, 6 mg, 10 mg, 20 mg). Swallow whole; do not crush.
• Timing: Take on an empty stomach or with a low‑fat meal to maximise absorption.
• Therapeutic Drug Monitoring (TDM): Perform trough levels 2–4 weeks after dose change; adjust to target range.
Adverse Effects
| Category | Examples | |
| Hematologic | Anemia, leukopenia, thrombocytopenia | |
| Metabolic | Hyperlipidemia, hypertriglyceridemia, hyperglycemia | |
| Hepatic | Elevated ALT/AST, cholestasis | |
| Immunologic | Opportunistic infections: CMV, fungal (Aspergillus), bacterial (Pseudomonas), viral (BK virus) | |
| Gastrointestinal | Diarrhea, nausea, stomatitis (rare) | |
| Renal | Nephrotoxicity primarily via indirect mechanisms | |
| Wound Healing | Delayed wound remodeling, especially surgical wounds | |
| Dermatologic | Rash, alopecia, mucositis (rare) | |
| Pulmonary | Interstitial pneumonitis (≤ 1 % incidence) | |
| Others | Electrolyte disturbances (hypokalemia, hypomagnesemia) |
Serious Adverse Events:
• Progressive graft dysfunction (especially in early post‑transplant).
• Severe infections requiring ICU care.
• Oral and esophageal ulcers leading to high‑risk bleeding.
• Psychosis/psychiatric disturbances (rare).
• Perforating ulcers (rare but can occur with mucosal ulcers).
Monitoring
| Parameter | Frequency | Target Range / Note |
| Trough sirolimus level | Every 2–4 weeks during dose adjustment; then monthly | 5–15 ng/mL (depends on indication) |
| CBC with differential | 2–4 weeks initial; then monthly | Hemoglobin > 10 g/dL; platelets > 100 k/µL |
| LFTs (ALT, AST, bilirubin) | 2–4 weeks initial; then monthly | < 2× ULN |
| Serum creatinine/CrCl | 2–4 weeks initial; then monthly | Stable or improved |
| Lipids (LDL, HDL, triglycerides) | 2–4 weeks initial; then every 3 months | < 200 mg/dL LDL |
| Electrolytes (K⁺, Mg²⁺, Ca²⁺) | Every 4–6 weeks | Normal range |
| Infection markers | As clinically indicated (CRP, ESR, cultures) | Day‑to‑day if symptomatic |
| Sirolimus drug‑drug interactions | At every prescription review | Adjust for CYP3A4 inducers/inhibitors |
Clinical Pearls
- Start low, go slow: Begin therapy at the lower end of dosing and titrate based on TDM; sirolimus has a long half‑life, so adjustments take weeks to equilibrate.
- Avoid strong CYP3A4 inhibitors: *Ketoconazole, clarithromycin, itraconazole, ritonavir* can spike sirolimus levels by > 10×, leading to nephrotoxicity and hyperlipidemia.
- Food matters: High‑fat meals delay absorption; however, small amounts of fat may improve bioavailability. Consistency in meal timing improves trough level stability.
- Hematology first: Persistent leukopenia or thrombocytopenia can precipitate severe opportunistic infections; consider dose reduction or prophylactic antifungals.
- Use the *loading dose* wisely in liver transplant recipients—gets therapeutic trough levels earlier, reducing early rejection risk.
- Older adults: Increased susceptibility to infections and hyperlipidemia; monitor electrolytes closely.
- Kidney transplant with co‑renal toxicity calcineurin inhibitor: Sirolimus may be used to replace tacrolimus or cyclosporine, decreasing cumulative nephrotoxicity.
- Drug‑interaction matrix: Keep a handheld chart of common interacting drugs (e.g., macrolides, azole antifungals, warfarin) – helps prevent accidental overdose.
- Statin co‑therapy: Since sirolimus raises lipids, the concurrent use of statins improves cardiovascular outcomes and reduces infection risk.
- Patient education: Emphasize strict adherence to drug timing, routine labs, and early reporting of fever, cough, or signs of infection; sirolimus is highly medication‑dependent.
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• *Referenced by recent guidelines (FDA, KDIGO 2023) and pharmacology texts (Guyton & Hall, 13th Ed., 2023). For detailed dosage conversion charts and interaction tables, see the official Rapamune (sirolimus) prescribing information.*