Usage
Sirolimus is an immunosuppressant primarily prescribed for the prophylaxis of organ rejection in patients receiving renal transplants. It is also used to treat lymphangioleiomyomatosis (LAM), a rare lung disease affecting primarily women. It is classified as an immunosuppressant and mTOR inhibitor. Sirolimus inhibits mTOR, a key regulatory protein kinase involved in cell growth and proliferation, thus suppressing the immune response and preventing rejection.
Alternate Names
Sirolimus is also known as Rapamycin. Brand names include Rapamune and others.
How It Works
Pharmacodynamics: Sirolimus binds to the immunophilin FKBP12, forming a complex that inhibits mTOR. This inhibition blocks signal transduction pathways crucial for T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation. Consequently, the immune response against the transplanted organ is suppressed.
Pharmacokinetics:
- Absorption: Sirolimus is absorbed orally with a bioavailability of approximately 14% for the oral solution and 17% for tablets. Food can affect absorption; therefore, it should be taken consistently with or without meals. Peak concentrations occur around 1-3 hours after oral administration.
- Distribution: Sirolimus is highly distributed throughout the body, extensively partitioning into formed blood elements. Its mean blood-to-plasma ratio is approximately 36. The volume of distribution is large (approximately 12 to 23 L/kg).
- Metabolism: Sirolimus is primarily metabolized by the liver via CYP3A4 enzymes, undergoing o-demethylation and hydroxylation. Several major metabolites are formed, some with immunosuppressive activity.
- Elimination: Sirolimus has a long elimination half-life, averaging around 60-80 hours. It is mainly excreted in the feces, with a small portion eliminated in urine.
Mode of Action: Sirolimus binds to FKBP12, creating a complex that inhibits mTOR. This inhibition specifically targets the signaling pathways activated by IL-2, IL-4, and IL-15, preventing cell cycle progression and lymphocyte proliferation crucial for mounting an immune response.
Receptor Binding/Enzyme Inhibition: The primary mechanism involves binding to FKBP12 and subsequent inhibition of mTOR. It does not directly inhibit calcineurin, unlike other immunosuppressants.
Elimination Pathways: Predominantly fecal excretion, with minor renal elimination. Metabolism is primarily hepatic, involving CYP3A4 enzymes.
Dosage
Standard Dosage
Adults:
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Renal Transplant Prophylaxis: Initial loading dose of 6 mg (low immunologic risk) or 15 mg (high immunologic risk), followed by a daily maintenance dose of 2 mg or 5 mg, respectively. Doses should be adjusted to maintain trough blood concentrations within the desired range (typically 5-15 ng/mL).
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Lymphangioleiomyomatosis: Initial dose of 2 mg daily, adjusted based on trough blood concentrations (5-15 ng/mL).
Children:
- Renal Transplant Prophylaxis: Loading dose of 3 mg/m² orally, followed by a maintenance dose of 1 mg/m²/day.
- Other uses: Pediatric dosing must be determined by the physician based on body surface area, age, and clinical condition.
Special Cases:
- Elderly Patients: Dosage adjustments may be needed based on organ function.
- Patients with Renal Impairment: No dosage adjustment is typically required.
- Patients with Hepatic Dysfunction: Reduced maintenance dose is necessary.
- Patients with Comorbid Conditions: Dosage adjustments should be made based on individual patient factors.
Clinical Use Cases Sirolimus is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indications are limited to organ transplant prophylaxis and LAM.
Dosage Adjustments Dosage must be individualized and adjusted to maintain trough concentrations within therapeutic range based on patient factors (e.g., renal/hepatic impairment, drug interactions, clinical response).
Side Effects
Common Side Effects: Peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, elevated creatinine, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, thrombocytopenia, acne, oral ulcers, impaired wound healing.
Rare but Serious Side Effects: Angioedema, interstitial lung disease, infections (including PML), malignancies (lymphoma, skin cancer), anaphylaxis, hepatic artery thrombosis, renal artery stenosis, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).
Long-Term Effects: Increased risk of infections, malignancies, renal dysfunction, hyperlipidemia.
Contraindications
Hypersensitivity to sirolimus, pregnancy (unless benefits clearly outweigh risks), breastfeeding (recommended to discontinue breastfeeding). Use with caution in patients with liver or lung transplants due to potential severe complications.
Drug Interactions
Sirolimus is primarily metabolized by CYP3A4 and is a substrate for P-glycoprotein. Avoid strong CYP3A4 inducers (e.g., rifampin, carbamazepine) and strong CYP3A4 inhibitors (e.g., ketoconazole, erythromycin). Caution with moderate CYP3A4 inhibitors/inducers. Interactions may occur with various medications including azole antifungals, macrolides, HIV protease inhibitors, grapefruit juice.
Pregnancy and Breastfeeding
Sirolimus is contraindicated in pregnancy due to potential teratogenic effects. Effective contraception is mandatory during and for 12 weeks after treatment. Breastfeeding is not recommended as sirolimus may be excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Inhibits mTOR, suppressing T-lymphocyte activation and proliferation.
- Side Effects: Edema, hyperlipidemia, hypertension, renal dysfunction, infections.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding, liver/lung transplant.
- Drug Interactions: CYP3A4 and P-gp interactions (numerous drugs).
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Individualized based on indication and patient-specific factors.
- Monitoring Parameters: Sirolimus trough levels, renal function, lipid profile, complete blood count.
Popular Combinations
Sirolimus is often used in combination with cyclosporine and corticosteroids in renal transplant patients.
Precautions
Assess renal and hepatic function before initiation. Monitor for infections and malignancies. Screen for hyperlipidemia and hypertension. Caution with live vaccines. Wound healing may be impaired.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Sirolimus?
A: Dosage is individualized based on the clinical indication (renal transplant vs. LAM), patient age, weight or body surface area, and concomitant medications.
Q2: How should Sirolimus be administered?
A: Administer orally once daily, consistently with or without food, at the same time each day.
Q3: What are the key monitoring parameters for patients on Sirolimus?
A: Sirolimus trough blood levels, complete blood counts, renal function tests, lipid profile, and blood pressure should be monitored regularly.
Q4: What are the most serious side effects of Sirolimus?
A: Serious side effects include increased susceptibility to infections (including PML), potential for malignancies (lymphoma, skin cancer), angioedema, interstitial lung disease, and renal dysfunction.
Q5: Can Sirolimus be used in patients with hepatic impairment?
A: Yes, but the maintenance dose should be reduced based on the degree of impairment.
Q6: What are the major drug interactions with Sirolimus?
A: Sirolimus interacts with strong CYP3A4 inhibitors and inducers, affecting its blood levels. Grapefruit juice should also be avoided.
Q7: Can Sirolimus be used during pregnancy or breastfeeding?
A: Sirolimus is contraindicated during pregnancy due to potential teratogenic effects. Breastfeeding is not recommended.
Q8: What is the mechanism of action of Sirolimus?
A: Sirolimus inhibits mTOR, a key regulatory protein kinase involved in T-lymphocyte activation and proliferation, thus suppressing the immune response.
Q9: What is the role of therapeutic drug monitoring in Sirolimus therapy?
A: Therapeutic drug monitoring of sirolimus trough levels is essential for optimizing efficacy and minimizing toxicity, especially during initial therapy and after dosage adjustments.
