Sirolimus dosing

Organ rejection Prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunological risk, cyclosporine should be withdrawn 2 to 4 months after transplantation and sirolimus dose should be increased to reach recommended blood concentrations. 

The manufacturers of sirolimus note that cisapride and metoclo-pramide may increase sirolimus levels, although there do not appear to be any published reports of this interaction. No significant pharmacokinetic interaction has been found with aci-clovir, digoxin, glibenclamide or co-trimoxazole. There is an isolated case report of atorvastatin increasing sirolimus trough serum levels twofold in one patient, and a reduction in the sirolimus dose was required. ... 

Two case reports describe increased sirolimus dose requirements in the presence of phenytoin. 

DES System / Manufacturer Stent Material Stent support duration / biodegradation (months) Sirolimus Dose Sirolimus Release (%, days)... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

For patients undergoing PCI and receiving stents, the recommended dose is 325 once daily for at least 30 days with bare metal stents, for 3 months with a sirolimus-eluting stent, and for 6 months with a paclitaxel-eluting stent, followed by 75 to 162 mg once daily thereafter. 

Sirolimus and cyclosporine combination therapy Administer the initial dose as soon as possible after transplantation. For de novo transplant recipients, give a loading dose P.1151... 

Hepatic function impairment Reduce the maintenance dose of sirolimus by approximately 33% in patients with hepatic function impairment. It is not necessary to modify the sirolimus loading dose. 

Bottles - Use the amber oral dose syringe to withdraw the prescribed amount of sirolimus oral solution from the bottle. Empty the correct amount of sirolimus from P.1152... 

Absorption - Sirolimus is rapidly absorbed following oral administration, with a mean time-to-peak concentration of approximately 1 hour after a single dose in healthy subjects and approximately 2 hours after multiple oral doses in renal transplant recipients. The systemic bioavailability of sirolimus was estimated to be approximately 14%. 

Excretion - After a single dose of sirolimus in healthy volunteers, 91 % was recovered from the feces and 2.2% was excreted in urine. 

Lymphocele Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in sirolimus-treated patients. Consider appropriate postoperative measures to minimize this complication. 

Black patients had higher rejection rates (56% vs 13%) than non-blacks given same regimen no significant differences in trough sirolimus concentrations at equal doses between blacks and non-blacks... 

Whole-blood sirolimus levels (drawn 1 hr prior to next dose), 5-7 days after initiation or dose change. Maintain levels at 10-15 ng/ml for first month, then consider increasing to 15-20 ng/ml, especially in patients receiving little cyclosporine... 

Rapamycin, also known as sirolimus, is a new macrolide antibiotic that interacts with cellcycle regulating proteins and inhibits cell division. The main side effects are thrombocytopenia and hyperlipidaemia. There is also evidence that it causes interstitial pneumonitis, which may resolve on withdrawing the drug or dose reduction. The drug is currently being assessed for combination therapy with tacrolimus or cyclosporin. 

De novo transplant recipients, a loading dose of sirolimus of 3 times the maintenance dose should be given. A daily maintenance dose of 2 mg is recommended for use in renal transplant patients, with a loading dose of 6mg. 

Sirolimus solution - For simultaneous administration, the mean i i and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus msx AUC were increased by 37% and 80%, respectively, comparedto sirohmiis alone. Cyclosporine clearance was reduced only after multiple-dose administration over 6 months. 

Azathioprine is administered to patients who do not respond to calcineurin inhibitors, sirolimus and glucocorticoids. Daily doses of 3-10 mg/kg of azathioprine are administered 1 or 2 days before renal transplantation or on the day of surgery for prophylactic therapy. Mycophenolate mofetil is increasingly used in place of azathioprine for tissue transplantation since it is less myelotoxic and causes few opportunistic infections. 

The most striking consequence of treatment with sirolimus is dose-dependent hyperlipidemia with significant increases in both cholesterol and triglyceride serum concentrations, which resolve after dosage reduction or sirolimus withdrawal (1065). 

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