sirolimus and Fever

Sirolimus is an immunosuppressive medication used in transplant recipients. To our knowledge, we describe the third reported case of alveolar hemorrhage in association with sirolimus. Fever, dyspnea, hemoptysis, and lung infiltrates resolved rapidly with cessation of sirolimus therapy both initially and after reinstitution of the drug. Unlike previous reports, our patient had no evidence of lymphocytic alveolitis but rather marked macrophage hemosiderosis, suggesting that sirolimus pulmonary toxicity may manifest through 2 separate mechanisms. Our case highlights an uncommon but potentially lethal manifestation of sirolimus pulmonary toxicity.

Topics: Biopsy; Bronchoalveolar Lavage Fluid; Dyspnea; Female; Fever; Hemoptysis; Hemorrhage; Hemosiderin; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases; Macrophages; Middle Aged; Pulmonary Alveoli; Sirolimus; Tomography, X-Ray Computed

Myelodysplastic syndrome (MDS) continues to cause major morbidity and mortality; thus, novel treatments are needed. The mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) inhibits cellular pathways important to MYC protein stability and cell growth. Pharmacodynamic biomarkers could be useful in distinguishing between (1) disease resistance that occurs even though mTOR is successfully inhibited (suggesting a need for a different treatment strategy) and (2) resistance that might respond to changes in drug dosage or schedule.. This was a small phase II trial of RAD001 in patients with low- and intermediate-1-risk MDS (n = 7). Protein S6K1 (S6) is downstream of mTOR, whereas protein kinase B (AKT) is upstream of mTOR. Therefore, to evaluate the pharmacodynamic effects of RAD001, S6 and AKT phosphorylation (pS6, pAKT) were measured by peripheral blood flow cytometry.. Sequential weeks of RAD001 produced a decrease in pS6, whereas pAKT was maintained or increased. There were no clinical responses despite the biomarker evidence of intended pharmacodynamic effect.. The pS6:pAKT ratio could be useful as a biomarker of target inhibition by RAD001 (clinicaltrials.gov identifier: NCT00809185).

Topics: Aged; Aged, 80 and over; Biomarkers; Cell Line, Tumor; Drug Administration Schedule; Dyspnea; Everolimus; Fatigue; Female; Fever; Flow Cytometry; Humans; Immunosuppressive Agents; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).. These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.. Novartis Pharmaceuticals.

Topics: Adolescent; Adult; Astrocytoma; Child; Child, Preschool; Double-Blind Method; Everolimus; Female; Fever; Humans; Infant; Male; Oral Ulcer; Seizures; Sirolimus; Stomatitis; Treatment Outcome; Tuberous Sclerosis; Young Adult

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.. Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.. Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.. The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.

Topics: Adult; Aged; Anti-Allergic Agents; Antineoplastic Agents; Area Under Curve; Carcinoma, Renal Cell; Colorectal Neoplasms; Diarrhea; Diphenhydramine; Disorders of Excessive Somnolence; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hyperglycemia; Hypertriglyceridemia; Hypophosphatemia; Infusions, Intravenous; Intestinal Perforation; Kidney Neoplasms; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Premedication; Sirolimus; Stomatitis; Treatment Outcome

Topics: Aged; Ascites; Cough; Drug Therapy, Combination; Erdheim-Chester Disease; Female; Fever; Glucocorticoids; Humans; Immunosuppressive Agents; Middle Aged; Prednisolone; Radionuclide Imaging; Sirolimus; Tomography, X-Ray Computed

There are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013.. An observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose.. Five cases of acute sirolimus overdose were reported--three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range.. Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.

Topics: Adolescent; Alkaline Phosphatase; Child, Preschool; Cholesterol; Drug Overdose; Female; Fever; Gastroenteritis; Humans; Infant; Male; Middle Aged; Retrospective Studies; Sirolimus; Suicide, Attempted

Topics: Acute Lung Injury; Aged; Fatal Outcome; Fever; Humans; Immunosuppressive Agents; Male; Pulmonary Edema; Sirolimus

Topics: Acute Disease; Adult; Chemical and Drug Induced Liver Injury; Fatal Outcome; Fever; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Sirolimus; Transplantation, Homologous

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

Topics: Fever; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Radiography, Thoracic; Sirolimus; Treatment Outcome

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.

Topics: Cyclosporine; Demyelinating Diseases; Female; Fever; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Sirolimus

Calcineurin inhibitors are one of the most common drugs used for prevention of acute rejection in recipients of renal allografts. New immunosuppressors have reduced the incidence of acute renal allograft rejection. There have been numerous recent attempts to develop alternative patterns of immunosuppressors for prevention of chronic renal allograft failure, and enhancing its survival. We described a patient who developed numerous complications after the initial postransplant period. He was treated with a calcineurin inhibitors-free immunosuppression in order to avoid nephrotoxicity, but had over 30 ng/ml of sirolimus. Renal function was impaired after cyclosponne withdrawal. Sirolimus was used in association with mycofenolate mofetil and prednisone.

Topics: Adult; Calcineurin Inhibitors; Comorbidity; Cyclosporine; Drug Therapy, Combination; Fever; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone; Pyelonephritis; Recurrence; Sirolimus; Ureteral Diseases; Urinary Bladder Fistula; Urinary Fistula

Topics: Aged; Azathioprine; Cardiomyopathy, Dilated; Drug Therapy, Combination; Everolimus; Fever; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Sirolimus