A Comparative Study of Sirolimus Tablet Versus Oral Solution for Prophylaxis of Acute Renal Allograft Rejection

Abstract

This multicenter, open-label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24-hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy-confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady-state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus t(max) after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus C(min,TN) and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.

Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts

“…Based on the 1-year results presented herein, variability in sirolimus trough concentrations was observed, although mean trough concentrations over time were consistent. Overall, these results are consistent with what has been observed in studies conducted in patients with renal allografts [22,24] and in healthy volunteers [25]. As noted in the results, 6 patients were studied on both occasions.…”

Accelerated Wound Healing by mTOR Activation in Genetically Defined Mouse Models

“…mTOR inhibitors such as rapamycin (serolimus) have been used in combination with cyclosporine or tacrolimus in the clinic since 1999 for decreasing the risk of acute allograft rejection episodes, as it helps preserve the long-term renal function better than high doses of cyclosporine (CsA) alone [26], [30]. The need to activate mTOR as part of the normal cutaneous healing process may now explain why mTOR inhibitors can cause a delay in wound closure as recently reported [21], [26].…”

Clinical Application of Development of Nonantibiotic Macrolides That Correct Inflammation-Driven Immune Dysfunction in Inflammatory Skin Diseases

“…This inhibitory effect can be partly explained because of a reduction of the phosphorylation of eIF-4e binding protein 1 (4E-BP1), a repressor of cap-mediated translation in mammalian cells [74]. Since 1999, rapamycin has been broadly used in human skin transplantation because it carries a low risk of renal dysfunction and reduces the risk of allograft rejection in comparison with other [75–77]. …”