sirolimus and Headache

Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function.. This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks.. Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV. The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials.. ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov.

Topics: Adult; Aged; Autophagy; Diarrhea; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Female; Forced Expiratory Volume; Headache; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lymphangioleiomyomatosis; Middle Aged; Mucositis; Sirolimus; Treatment Outcome; Vascular Endothelial Growth Factor D; Vital Capacity; Walk Test

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

To quantify the influence of a high-fat meal on the oral bioavailability of the immunosuppressant everolimus in a single-dose study in healthy subjects and to confirm the results in a small food-effect screening assessment in patients with renal transplants who were receiving multiple-dose everolimus.. Randomized, open-label, crossover, single-dose study and confirmatory screening.. Phase 1 unit for the single-dose study and two German hospitals for the patient screening.. Twenty-four healthy male volunteers; six clinically stable patients with renal transplants who were originally part of a phase I dose-escalation study.. The 24 healthy men received everolimus 2 mg orally under fasting conditions and after a high-fat meal. The six patients received everolimus 2.5 mg/day orally, in addition to cyclosporine and prednisone. On two occasions, a pharmacokinetic profile was obtained over the dosing interval after drug administration under fasting conditions and after a high-fat meal in a randomized sequence.. In the single-dose study in healthy subjects, a high-fat meal delayed everolimus time to maximum concentration (Tmax) by a median 1.25 hours, reduced peak blood concentration (Cmax) by 60%, and reduced area under the concentration-time curve (AUC) by 16%. In the multiple-dose screening in patients with renal transplants, a high-fat meal delayed Tmax by a median 1.75 hours and reduced Cmax by 53% and AUC by 21%. Everolimus trough levels showed no food effect, whereas the peak-trough fluctuation was dampened by 52%.. A high-fat meal modestly reduced everolimus AUC. To minimize longitudinal variability in exposure, everolimus should be administered consistently either with food or without food.

Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Cyclosporine; Dietary Fats; Drug Interactions; Everolimus; Fasting; Half-Life; Headache; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Prednisone; Sirolimus; Time Factors

Topics: Administration, Oral; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Headache; Humans; Immunosuppressive Agents; Placebos; Polyenes; Sirolimus

Topics: Basilar Artery; Brain Infarction; Cerebellum; Cerebral Arteries; Disease Progression; Emphysema; Female; Headache; Hemianopsia; Humans; Hypertension; Immunosuppressive Agents; Intracranial Hemorrhage, Hypertensive; Kidney Neoplasms; Lung Transplantation; Magnetic Resonance Imaging; Middle Aged; Occipital Lobe; Posterior Cerebral Artery; Sirolimus