Potential age-dependent changes of sirolimus metabolite patterns in pediatric renal transplant recipients remain elusive. Thirteen pediatric solid organ transplant recipients (10 kidney, one combined liver-kidney, two liver, mean age 8.0 +/- 5.0 yr) underwent a sirolimus pharmacokinetic profile in steady-state with 10 samples drawn over 12 h post-intake to calculate the AUC(0-12 h). Concentrations of sirolimus and metabolite were quantified using a validated LC-MS/MS assay and metabolite structures were identified directly in blood extracts using LC-MS/iontrap. Average sirolimus AUC(0-12 h) was 64.9 +/- 29.7 ng h/mL. Median (range) AUC(0-12 h) for each metabolite (ng h/mL) was: 12-hydroxy-sirolimus 7.6 (0.2-18.8), 46-hydroxy sirolimus 3.1 (0.0-12.4), 24-hydroxy sirolimus 4.3 (0.0-12.6), piperidine-hydroxy sirolimus 3.5 (0.0-8.3), 39-O-desmethyl sirolimus 3.6 (0.0-11.3), 16-O-desmethyl sirolimus 5.0 (0.1-9.9), and di-hydroxy sirolimus 4.3 (0.0-32.5). The metabolites reached a median total AUC(0-12 h) of 60% of that of sirolimus. The range was 2.6-136%, indicating significant variability. In all, 77.5% of the metabolites were hydroxylated, while 39-O-desmethyl sirolimus accounted for only 8.4% of the AUC(0-12 h). This is clinically relevant as 39-O-desmethyl sirolimus shows 86-127% cross-reactivity with the antibody of the widely used Abbott sirolimus immunoassay. The metabolism of sirolimus in the children included in our study differed from that reported in adults, which should be considered when monitoring sirolimus exposure immunologically.

We describe the first case of sirolimus-induced drug fever in a female liver transplant recipient, with a history of hepatitis C-induced end-stage liver cirrhosis in 1999. In 2005, six years after transplantation, she developed calcineurin inhibitor-induced renal function impairment. Immunosuppression was switched from tacrolimus to sirolimus. Two days after the intake of sirolimus, she developed daily fever spikes, but no infectious focus was found. Antibiotic therapy had no influence on the fever. After fourteen days, sirolimus was switched back to tacrolimus and the fever disappeared. In history, the patient developed ciclosporin-induced generalized seizures eleven days after liver transplantation, followed by the development of a motoric speech disorder. Magnetic resonance imaging (MRI) findings were consistent with leucoencephalopathy, therefore immunosuppressive therapy was changed from ciclosporin to tacrolimus and the neurologic symptoms improved significantly. Our case is the first reported case of sirolimus-induced drug fever. In addition, the patient showed the rare occurrence of ciclosporin-induced leukencephalopathy with seizures.

Neurological complications are common in transplant recipients treated with immunosuppressant calcineurin inhibitors. Rapamycin, a macrolide antibiotic, was suggested as an alternative agent in patients who develop calcineurin inhibitor associated neurotoxicity, including seizure attacks. The aim of the present study was to test the effect of rapamycin on the bioelectrical activity and evoked field excitatory postsynaptic potentials (fEPSP) in CA1 area of hippocampal tissues and compare its effect with FK506, a calcineurin inhibitor agent. Application of rapamycin at different concentrations neither affected the bioelectrical activity nor changed fEPSP magnitude. In contrast, FK506 elicited epileptiform burst discharges and significantly enhanced fEPSP magnitude. This study supports the suggestion that rapamycin could be used as an alternative to calcineurin inhibitors in the event of neurotoxicity.

In adult renal recipients, coadministration of tacrolimus (TAC) and sirolimus (SIR) results in reduced exposure to TAC at SIR doses of 2 mg/day. Eight pediatric renal recipients (median age at transplant 2.0 years, range: 1.2-12.9 years) were converted to TAC- and SIR-based immunosuppression as a rescue therapy. All patients had biopsy-proven chronic allograft nephropathy. TAC levels were measured using a commercially available EMIT assay and SIR levels with a newly developed assay based on the LC-MS MS technology. SIR was started at 0.13+/-0.05 mg/kg/day (3.51+/-1.26 mg/m2/day) in two divided doses. TAC was given at 0.14+/-0.09 mg/kg/day, resulting in a trough level of 6.3+/-2.5 ng/mL. After the addition of SIR, the median dose required to keep TAC blood trough concentrations within the target range increased by 71.2% (range: 21.9-245.4%), dose-normalized TAC exposure (AUC) decreased to 67.1% and the dose-normalized C(max), a surrogate for absorption rate, to 53.8% (both geometric means) while terminal half-life (t1/2), a pharmacokinetic parameter characterizing systemic elimination, remained unchanged (p<0.93). Adding SIR to TAC-based immunosuppression in young pediatric renal transplant recipients results in a significant decrease of TAC exposure. TAC trough levels should be monitored frequently.

A 19-year-old woman was admitted to receive a kidney transplant from a nonliving donor. At the time of transplantation, she was taking oral phenytoin 300 mg every morning, 100 mg at noon, and 300 mg every evening (total of 700 mg/day) to treat seizures secondary to hemodialysis. Immediately after the transplantation, phenytoin treatment was resumed, and immunosuppressive therapy consisting of antithymocyte globulin, cyclosporine, mycophenolate mofetil, and corticosteroids was started. Her cyclosporine blood levels varied over the first 10 days after transplantation. Cyclosporine was discontinued, and tacrolimus was begun after acute rejection was discovered. The rejection was treated with antithymocyte globulin, plasmapheresis, and intravenous immunoglobulin, and subsequently resolved; however, the patient's blood concentrations of tacrolimus varied widely. Phenytoin is an antiepileptic drug that induces hepatic enzymes, affecting the cytochrome P450 3A family. These enzymes metabolize approximately 50% of all prescribed drugs, including cyclosporine and tacrolimus. According to the Naranjo adverse drug reaction probability scale, this patient's adverse drug reaction probably occurred from altered metabolism of cyclosporine and tacrolimus due to phenytoin therapy. Clinicians must identify drug interactions between metabolic enzyme inducers or inhibitors and drug substrates with narrow therapeutic ranges, closely monitor drug concentrations, and observe patients for clinical signs and symptoms of therapeutic failure or toxicity. In daily practice, clinicians should explore the metabolic characteristics of drugs and their biotransformation pathways to identify patients who require alternative therapy.

Sirolimus is primarily used as a rescue agent in pediatric transplant recipients, particularly in cases of cyclosporine or tacrolimus toxicity. Preliminary data indicate a higher apparent oral clearance in younger children (4-10 years of age). Various drug interactions have been described between sirolimus and drugs that are substrates/inhibitors or inducers of CYP3A and the P-glycoprotein transporter. Close monitoring of trough sirolimus blood levels is therefore recommended for pediatric transplant recipients. In de novo adult kidney transplant recipients on triple therapy with cyclosporine, corticosteroids and sirolimus, a therapeutic window of 4-12 microg/l is recommended for sirolimus trough concentrations determined by HPLC or LC/MS-MS. In maintenance adult patients after conversion to a calcineurin inhibitor-free regimen, sirolimus trough concentrations of 5-10 microg/l are proposed in combination with mycophenolate mofetil. These therapeutic ranges may also serve as a guide for pediatric renal transplant recipients. The concept of C2 monitoring still needs to be critically evaluated in pediatric patients. The crucial importance of achieving an adequate cyclosporine exposure early after transplantation has been demonstrated for adult transplant recipients. A cyclosporine concentration taken 2 h after dosing is a good surrogate marker of the AUC0-4h in adults. Various clinical studies have shown that in pediatric patients, the C2 concentration shows a substantially better correlation with cyclosporine exposure compared to the trough level (C0). In an outcome study with pediatric renal transplant recipients, it could be demonstrated that the AUC(0-4h) was a predictor of acute rejection in the first 3 weeks after transplantation, whereas C2 levels showed no significant association. Abbreviated AUC strategies may be preferable for optimization of CsA exposure in pediatric patients.

Sirolimus therapy has been used in orthotopic liver transplant (OLT) recipients diagnosed with a variety of diseases; chronic graft rejection (CR), calcineurin associated renal toxicity, preemptive immune suppression, calcineurin related neurotoxicity, preemptive therapy in transplant recipients with history of hepatocellular carcinoma, and steroid resistant allograft rejection.

A search for the medical literature and experiences involving sirolimus was done.

Several animal and human reports evaluating the use sirolimus in liver transplant recipients are found and discussed.

Sirolimus has been used for multitude of indications, primarily based on anecdotal experiences. However, reports of sirolimus related side effects have decreased the transplant communities' enthusiasm towards promoting this agent as a safe immune suppression agent.

This report documents that coadministration of phenytoin leads to decreased blood concentrations and area under the blood concentration-time curve of sirolimus in a liver transplant patient. It is essential to monitor the blood concentrations of sirolimus and adjust the sirolimus dosage when phenytoin administration begins or ends.