Neurotoxicity is a well-recognized side effect of calcineurin inhibitors. Rapamycin is considered to be significantly less neurotoxic than calcineurin inhibitors (CNIs). The aim of this study was to retrospectively analyze a group of post-liver transplant patients who had been converted to rapamycin because of CNI-related neurotoxicity.Orthotopic liver transplantation (OLT) was performed in 56 consecutive patients between April 1, 2003, and August 15, 2004. Immunosuppression was administered with tacrolimus, mycophenolic acid, and corticosteroids.Seven patients were converted to rapamycin due to new-onset neurotoxicity or exacerbation of previous neurological symptoms secondary to CNI. None of the patients had toxic levels tacrolimus (>15 ng/mL) at the time of symptoms, which persisted despite reduction of CNI dose. The indications for conversion were: (1) peripheral neuropathy; (2) seizure; (3) metabolic encephalopathy; and (4) central pontine myelinolysis. All patients showed improvement or resolution of their neurological symptoms after conversion to rapamycin. Two patients died, the first due to a hypoxic event and the second due to central pontine myelinolysis with limited improvement and a family decision to withdraw care. There were no complications directly attributed to rapamycin. Specifically, there were no thrombotic events, wound complications, or biliary leaks. Three patients had a rejection episode that was successfully treated with pulse corticosteroids and low-dose tacrolimus (levels < 5 ng/mL).Rapamycin can be safely used in OLT recipients with severe neurological symptoms ascribed to or exacerbated by CNIs. Rapamycin monotherapy may be inadequate to control rejection early after transplantation. Rapamycin can be combined with low doses of CNI to prevent rejection.

The present study evaluated whether the addition of sirolimus to a cyclosporine (CyA)/prednisone (Pred) regimen mitigated the greater proclivity to acute rejection episodes and graft loss characteristic of African-American renal transplant recipients. Using Kaplan-Meier and log-rank tests, African-American renal transplant recipients treated with either CyA/Pred (n = 90) or sirolimus/CyA/Pred (n = 47) were compared with 120 Caucasian patients treated with sirolimus/CyA/Pred for 2-year rates of patient and graft survival as well as acute rejection episodes. Mean laboratory values were compared using analysis of variance and F-tests. Addition of sirolimus to the CyA/Pred regimen reduced the incidence of acute rejection episodes in African-Americans from 43.3 % to 19.2 % (P = 0.004), a value similar to Caucasian patients. The 97.9 % 2-year graft survival rate among 47 African-American patients treated with sirolimus/CyA/Pred was significantly higher than the 85.6 % rate shown among the 90 CyA/Pred-treated African-American transplant recipients (P = 0.0479) and similar to that in Caucasians. The 95.7 % patient survival rate among the African-American sirolimus/CyA/Pred group was similar to the 97.8 % rate in the African-American CyA/Pred cohort. Interestingly, there was no evident toxicity from the addition of sirolimus. The addition of sirolimus to a CyA-based regimen reduced acute rejection episodes and graft loss experienced by African-American renal transplant recipients.

We sought to examine the potential benefits of therapeutic drug monitoring of sirolimus, a potent immunosuppressive agent that displays a pleiotropic array of side effects. Methods. A high‐performance liquid chromatography (LC) procedure combined with ultraviolet detection (UV) was used to measure serial concentrations of parent compound sirolimus in 150 renal transplant recipients over a period of 4 yr. Drug concentrations in whole blood at trough time, as well as within pharmacokinetic profiles, were correlated with clinical events using contingency tables, logistic regression analysis, and receiver operating characteristic (ROC) curves. Results. The LC/UV method showed an excellent correlation with detection of LC‐resolved components by tandem mass spectrometry, demonstrating that the LC/UV method selectively detected parent compound. Sirolimus displayed the characteristics of a critical‐dose drug: Its concentration could not be predicted by a standard body or demographic measure, or by dose, and it showed high degrees of intra‐ and inter‐individual variability. However, there was a good correlation between trough and area‐under‐the‐curve measurements. There was a significant association between trough values expressed as either observed (<5 ng/mL) or dose‐corrected parameter (<1.7 ng/mL per mg administered drug) and the occurrence and severity of acute rejection episodes – despite the low overall incidence of 23 episodes among the cohort of 150 patients. Similarly, ROC functions showed a correlation of the occurrence of hypertriglyceridemia, thrombocytopenia, and leukopenia, but not hypercholesterolemia, with trough concentrations above 15 ng/mL. Conclusion. Due to its behavior as a critical‐dose drug, therapeutic monitoring to measure sirolimus concentrations by a LC/UV method may provide clinicians with a tool to optimize outcomes.

Kahan, Barry D.1; Napoli, Kimberly L.1; Kelly, Patrick A.1,2; Podbielski, Jeanette1; Hussein, Iman1; Urbauer, Diana L.1; Katz, Stephen H.1; Buren, Charles T. Van1 Author Information