sirolimus and Abdominal-Pain

Sirolimus (Rapamune, rapamycin) has been shown to be an effective and safe immunosuppressive drug in adult kidney transplant patients when administered concomitantly with cyclosporine (CsA) and steroids. This study reports on a phase 1 assessment of the drug's tolerance, safety, and pharmacokinetic parameters in pediatric patients. The safety and pharmacokinetic profiles of ascending single doses of sirolimus oral solution were investigated in 32 clinically stable pediatric patients on chronic hemodialysis (n = 26) or peritoneal dialysis (n = 6). Patients were divided into two age groups (5-11 and 12-18 yr), and each patient received either a single dose of sirolimus (1, 3, 9, or 15 mg/m(2)) or placebo. Whole blood and plasma samples were collected from each patient for the determination of sirolimus pharmacokinetic parameters. Safety assessments were based on reports of adverse events and results of scheduled physical examinations, vital sign measurements and clinical laboratory tests. The younger patients (5-11 yr) showed statistically significant increases in whole blood sirolimus t(max) (p < or = 0.05) and weight-normalized CL/F (p<0.05) when compared with older patients (12-18 yr). There were no differences in terminal t(1/2), V(ss)/F, dose-normalized peak concentration (C(max)) and AUC, or the B/P. The whole blood sirolimus mean t(max) and weight-normalized CL/F in younger patients were increased by approximately 41.5% and 30%, respectively. Whole blood sirolimus concentrations exhibited less than proportional increases with ascending doses, which may have been caused by the large inter-subject variability in CL/F, small number of subjects, and a potentially inherent decrease in sirolimus bioavailability in younger pediatric patients. Adverse events occurred in all dose and age groups, with headache and stomach pain being the most frequently observed events. No deaths or serious adverse events were reported, and no patient withdrew from the study because of an adverse event. Based on an inter-study analysis, weight-normalized CL/F in the current population of younger pediatric dialysis patients (5-11 yr, 544 +/- 463 mL/h/kg, n = 7) was increased by 90% (p < or = 0.05) compared with healthy adults (19-36 yr, 287 +/- 111 mL/h/kg, n = 25). These results suggest that younger pediatric patients might require an increased maintenance dose of sirolimus to achieve whole blood exposures similar to those in healthy adults. Sirolimus is well tolerated as a sin

Topics: Abdominal Pain; Administration, Oral; Adolescent; Adult; Age Factors; Biological Availability; Child; Child, Preschool; Double-Blind Method; Female; Headache; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Peritoneal Dialysis; Placebos; Renal Dialysis; Safety; Sirolimus

An 18-year-old woman was admitted with abdominal pain and hematochezia. She was previously healthy until 15 years of age and was subsequently diagnosed with hypogammaglobulinemia, protein-losing enteropathy, a benign temporal lobe brain lesion/orbital fibroadenoma, autoimmune hepatitis, iron deficiency anaemia and hypothyroidism. She developed respiratory distress and hypoxemia. She was found to have nodules on chest CT scan. She was diagnosed with cytotoxic T-lymphocyte-associated antigen 4 deficiency via genetic testing.

Topics: Abatacept; Abdominal Pain; Adolescent; CTLA-4 Antigen; Diagnosis, Differential; Female; Gastrointestinal Hemorrhage; Humans; Immunosuppressive Agents; Multiple Pulmonary Nodules; Sirolimus; Treatment Outcome

Topics: Abdominal Pain; Adult; Anti-Bacterial Agents; Cephalosporins; Everolimus; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphocele; Male; Mycophenolic Acid; Prednisolone; Radiography; Scapula; Sirolimus; Tacrolimus; Ultrasonography

Pain induced by calcineurin inhibitors is a rare complication of unknown pathogenesis. We have reported herein a 7-year-old child who presented with abdominal pain, vomiting, and weight loss showing no significant findings after an extensive laboratory and imaging workup. After conversion from tacrolimus to sirolimus, there was complete resolution of the gastrointestinal symptoms and pain; the patient displays excellent renal function. Calcineurin inhibitor-induced pain syndrome is diagnosis of exclusion but must be considered because the withdrawal of this immunosuppressive agent is associated with improvement in symptoms and quality of life.

Topics: Abdominal Pain; Calcineurin Inhibitors; Child; Drug Substitution; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Tacrolimus; Treatment Outcome; Vomiting; Weight Loss

An 18-yr-old Hispanic female with end-stage renal disease secondary to chronic glomerulonephritis of unknown etiology underwent cadaveric renal transplantation. She was placed on a steroid-free protocol with tacrolimus and mycophenolate mofetil (MMF) for maintenance immunosuppression. Approximately 8 months post-transplantation, MMF was replaced by sirolimus (SRL) because of persistent leukopenia. Four months after the initiation of SRL, the patient began to experience chronic, constant periumbilical abdominal pain in the absence of vomiting, diarrhea or melena. Esophagogastroduodenoscopy and CT scans revealed significant diffuse mucosal thickening of the antrum, duodenum, and jejunum; leukocytoclastic vasculitis was identified on antral biopsy. A repeat biopsy after reduction of sirolimus dose by 50% over 6 months showed mild chronic inflammation of stomach and duodenum with some improvement in abdominal pain. Discontinuation of SRL and replacement with low dose MMF resulted in complete resolution of pain and normalization of gastrointestinal anatomy by imaging studies within 2 months. In light of this report, drug-induced leukocytoclastic vasculitis caused by SRL should be considered in the differential diagnosis of chronic abdominal pain in a patient with organ transplantation.

Topics: Abdominal Pain; Adult; Biopsy; Cadaver; Diagnosis, Differential; Female; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Vasculitis, Leukocytoclastic, Cutaneous