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Tejani A*, Alexander S, Ettenger R, Lerner G, Zimmerman J, Kohaut E, Briscoe DM. Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune®, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Pediatr Transplantation 2004: 8: 151–160. © 2004 Blackwell Munksgaard 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. [ABSTRACT FROM AUTHOR]

Abstract: We studied 124 children, 62 patient-subjects who had end-stage renal disease (ESRD) and 62 sibling-controls who closely matched the patient-subjects in terms of their ethnicity and their socioeconomic status, to discern whether children with ESRD would perform less well than their siblings on standardized achievement and intelligence quotient (IQ) tests, and to determine whether ethnicity would influence such results. The subjects were recruited from nine pediatric transplant and dialysis centers across the United States. Thirty-one subjects were white (Euro-American), 17 were African-American, and 14 were categorized as ‘other’. The average age of the patient-subjects was 13.7 ± 0.44 yr; and of the sibling-controls 13.7 ± 0.38 yr. Most patients (61%) and siblings (84%) were in regular school classes, and most (87% and 92%, respectively) attended school full-time. The average IQ percentile rank for the patients was significantly lower than their siblings (31 ± 4 vs. 44 ± 5, respectively, with normal = 50). Patients tended to score lower on achievement tests compared with their siblings (spelling: 88.7 ± 4 vs. 94.6 ± 2; arithmetic: 88.5 ± 2 vs. 94.0 ± 2; reading: 91.9 ± 2 vs. 100 ± 3, respectively). Patients scores on achievement tests were influenced by age at diagnosis and by the mother/caregiver's lower achievement. Also, increased time on dialysis predicted lower scores on achievement tests. Neither dialysis/transplant status nor ethnicity significantly affected outcome. Our data suggest that ESRD, but not ethnicity or dialysis/transplant status, is a risk factor for lower IQ and academic achievement, especially in younger children, in children who spend more time living with ESRD, and in children whose mother's/caregiver's have lower educational levels. [ABSTRACT FROM AUTHOR]

Recombinant human growth hormone post-renal transplantation in children: A randomized controlled study of the NAPRTCS. Background. Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken. Methods. Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment. Results. After one year, the delta SDS (standardized height) was +0.49 ± 0.10 in the treatment group (N = 30) compared to -0.10 ± 0.08 in the control group ( N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups. Conclusion. In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events. [ABSTRACT FROM AUTHOR]