Immunosuppression With Sirolimus After Solid Organ Transplantation in Children

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2006;12(2) 

In This Article

Clinical Experience in Children

Several case series have been published describing the use of sirolimus in pediatric transplant patients.[4,5,6,7,8,9,10,11] It has been used both in combination with a calcineurin inhibitor or with a mycophenolate/steroid regimen. In 2001, Sindhi and colleagues evaluated the efficacy and safety of sirolimus in 50 children (ages 19 days-21 years) with transplants, including 26 liver, 5 heart, 5 intestine, 9 liver/intestine, 1 lung, 1 bone-marrow, 1 liver/kidney, 1 multiorgan transplant, and 1 unspecified.[5] Forty-two children received sirolimus as rescue therapy after failing or developing toxicity to traditional immunosuppressive agents; the remaining eight children receiving sirolimus as primary therapy. Sirolimus was initiated at 1 to 2 mg/m2 given orally once daily. The mean period of follow-up was 204 days (range 18-800 days).

Of the 42 children given sirolimus as rescue therapy, 33 (80%) had resolution of their indication for rescue. In the primary treatment group, 7/8 (88.5%) had no episodes of rejection. The mean sirolimus trough concentration was 6.9 ± 5.5 ng/mL. Nine children (18%) discontinued sirolimus because of adverse effects, primarily anemia and leucopenia. In 23 children who were given sirolimus after developing tacrolimus-induced nephrotoxicity, serum creatinine decreased from a mean of 1.73 ± 0.6 to 1.2 ± 0.8 mg/dL. Overall, 38 of the 50 children (76%) experienced benefit. Forty-one (82%) remained on therapy at the Conclusion of the study, with 33 receiving a combination of tacrolimus and sirolimus and eight receiving sirolimus alone.[5]

Several other investigators have evaluated sirolimus in pediatric renal transplants.[6,7,8] Vilalta and colleagues gave six children (2 to 18 years of age) sirolimus as primary therapy in combination with cyclosporine, mycophenolate, and methylprednisolone.[6] The goal of this regimen was early withdrawal of cyclosporine, to minimize the risk of nephrotoxicity. Sirolimus was initiated at 1.15 mg/m2 daily and adjusted to maintain trough concentrations between 4 and 12 ng/mL. Therapeutic levels were reached between days 3 and 5. Cyclosporine was withdrawn during the first week after transplantation, as soon as sirolimus levels were at goal. No rejection episodes were reported, and all patients had normal creatinine values within 14 days of transplantation.

In 2002, Sindhi's group published additional experience with sirolimus in 45 pediatric liver transplants.[9] Fifteen children were given sirolimus as primary therapy and 30 as rescue therapy. When sirolimus was used as primary immunotherapy, six of the 15 children did not require steroids and another five tolerated early steroid withdrawal. In 12 of the 15 rescue patients who were receiving tacrolimus, the addition of sirolimus allowed for the elimination of tacrolimus. The mean sirolimus trough concentrations in the primary and rescue groups were 5.28 ng/mL and 5.1 ng/mL, respectively.

Sirolimus has also been used to prevent or improve the nephrotoxicity associated with calcineurin inhibitors in liver transplant patients, by allowing a reduction in cyclosporine or tacrolimus dose. Casas-Melley and coworkers conducted a retrospective review of 38 pediatric liver transplant patients (mean age 8.6 years) treated with sirolimus between January 2000 and February 2003.[12] In a subset of 11 children with renal impairment after tacrolimus use, the authors found a significant improvement in serum creatinine levels when sirolimus was added and the tacrolimus dose reduced (0.8 mg/dL on sirolimus compared to 1.3 mg/dL at baseline).

A recent paper from the researchers at the University of Toronto describes their experience with sirolimus in pediatric heart transplant recipients.[13] Sixteen patients (ages 5 to 18 years) were treated, with a median time of introduction of 2.7 years post-transplant (range 1 month to 8.2 years). Fifteen of the patients were receiving steroids, 15 were receiving tacrolimus, and 11 were receiving mycophenolate. The average daily maintenance dose of sirolimus to achieve trough concentrations within the desired range of 5 to 15 mcg/mL was 0.25 mg/kg (7 mg/m2). The six patients given sirolimus for rejection showed improvement in subsequent biopsies. Two of the three patients treated for tacrolimus-induced nephrotoxicity showed improvement in glomerular filtration rate after tacrolimus was reduced or removed. Adverse effects included hyperlipidemia (38%) abdominal pain (31%), mouth ulcers (26%), anemia or neutropenia (12.5%), pericardial effusion (6%), and interstitial lung disease (6%). Three children required discontinuation due to adverse effects. The authors concluded that sirolimus was a valuable agent for the management of pediatric transplant patients with rejection or in patients with adverse effects to other agents.[13]


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