Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune Ò , rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis 1 Tejani A*, Alexander S, Ettenger R, Lerner G, Zimmerman J, Kohaut E, Briscoe DM. Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune Ò , rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. PediatrTransplantation2004:8:151–160. Ó 2004BlackwellMunksgaard Abstract: Sirolimus (Rapamune Ò , 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 tol- erance, 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 ¼ 26) or peritoneal dialysis (n ¼ 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 £ 0.05) and weight-normalized CL/F (p<0.05) when compared with older pa- tients (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 pa- tient withdrew from the study because of an adverse event. Based on an Amir Tejani 1 *, Steven Alexander 2 , Robert Ettenger 3 , Gary Lerner 4 , James Zimmerman 5 , Edward Kohaut 6 and David M. Briscoe 7 1 Division of Pediatric Nephrology, SUNY Health Sciences Center, Renal Pediatrics Division, Brooklyn, NY, 2 Division of Pediatric Nephrology, University of Texas SW Medical Center, Department of Pediatrics, Dallas, TX, 3 Division of Pediatric Nephrology, UCLA Medical Center, Los Angeles, CA, 4 Division of Pediatric Nephrology, The Children's Hospital of Los Angeles, Los Angeles, CA, 5 Division of Pediatric Nephrology, Wyeth Research, Collegeville, PA, 6 Division of Pediatric Nephrology, The University of Alabama, Birmingham, AL, 7 Division of Pediatric Nephrology, The Children's Hospital, Boston, MA, USA Key words: sirolimus – rapamycin – immunosuppression – renal transplantation – pharmacokinetics – pediatric patients David M. Briscoe MD, c/o The North American Pediatric Renal Transplant Cooperative Study, 330 Brookline Ave, Span Building Suite 220, Boston, MA 02215, USA Tel.: 617-632-0730 Fax: 617-632-0733 E-mail: david.briscoe@childrens.harvard.edu Accepted for publication 9 October 2003 1 Abbreviations: AUC, total area under the plasma concentration–time curve; B/P, whole blood to plasma ratio; BSA, bovine serum albumin; CL/F, oral-dose clearance (dose/AUC); C max , peak concentration; CPK, creatine phosphokinase; CsA, cyclosporine; CYP3A4, cytochrome P-450 3A4; ECG, electrocardiogram; HCG, human chorionic gonadotropin; HCT, hematocrit value; LC/MS/MS, high-performance liquid chromatography/tandem-mass spectrometry; LDH, lactate dehydroge- nase;MRT,meanresidencetime;TEAE,treatment-emergentadverseevent; t 1/2 ,terminalphasedispositionhalf-life(0.693/k z );P- gp,P-glycoprotein; t max , time at which peak concentration occurs; V ss /F, oral-dose apparent steady-state volume of distribution. 1 Presented, in part, at the International Pediatric Transplant Society, September 2000, Venice, Italy. *Author is deceased. Pediatr Transplantation 2004: 8: 151–160 Printed in UK. All rights reserved Copyright Ó 2004 Blackwell Munksgaard Pediatric Transplantation 151