Immunosuppression With Sirolimus After Solid Organ Transplantation in Children

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2006;12(2) 

In This Article

Pharmacokinetics

After oral administration, sirolimus is rapidly absorbed, with an average time to peak serum concentrations in adults of 1 hour after initial dosing and 2 hours after repeated dosing. Systemic bioavailability is approximately 14% with the oral solution. Bioavailability with the tablet is 27% higher than that with the oral solution, indicating that the formulations are not bioequivalent. The two products have been found to be clinically equivalent at the 2 mg dose. Administration with food produces variable effects. Bioavailability of the oral solution is decreased when administered with a high-fat meal, but when the tablets are taken with a high-fat meal, bioavailability is increased.[2,3]

Sirolimus is widely distributed, with a mean volume of distribution of 12 ± 8 L/kg. It is highly bound (92%) to serum proteins, primarily albumin. Sirolimus is a substrate for cytochrome P450 3A4 (CYP3A4) in the intestinal wall and liver and undergoes counter-transport by P-glycoprotein. It is extensively metabolized through O-demethylation and hydroxylation, forming seven major metabolites. The mean elimination half-life for sirolimus in adult renal transplant patients is 62 ± 16 hours.[2,3]

The pharmacokinetic profile of sirolimus has also been studied in pediatric patients.[15] Data from several small trials have demonstrated a more rapid clearance in younger children. In a study of 21 transplanted children receiving sirolimus and tacrolimus, the mean half-life of sirolimus was 11.8 ± 5.5 hours, significantly shorter than that reported in adults.[4] These Results were replicated in a recent trial of 13 children, where the mean terminal half-life was found to be 10.8 hours after 1 month of sirolimus use and 12.1 hours after 3 months.[16]

In 2005, Filler and colleagues reported their experience adding sirolimus to a tacrolimus-based regimen in eight children with renal transplants.[8] The children were included in the treatment protocol after developing chromic nephropathy with their tacrolimus regimen. Sirolimus was initiated at 0.13 ± 0.05 mg/kg/day (3.51 ± 1.26 mg/m2/day) given in two divided doses. After adding sirolimus, tacrolimus concentrations decreased, requiring dosage adjustment. The mean sirolimus trough concentration was 6.19 ± 1.36 ng/mL, with a mean half-life of 17.5 ± 6.9 hours, significantly longer than previously reported in children. The authors suggested this difference in half-life may be the result of an interaction with tacrolimus.

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