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Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune®, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis 1

Abstract:  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/m2) 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 tmax (p ≤ 0.05) and weight‐normalized CL/F (p<0.05) when compared with older patients (12–18 yr). There were no differences in terminal t1/2, Vss/F, dose‐normalized peak concentration (Cmax) and AUC, or the B/P. The whole blood sirolimus mean tmax 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 ≤ 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 single dose of 1, 3, 9, or 15 mg/m2.