Safety and efficacy of TOR inhibitors in pediatric renal transplant recipients.
Information about the pharmacokinetics, safety, and efficacy of target of rapamycin (TOR) inhibitors, such as sirolimus and everolimus, in pediatric renal transplant recipients is limited. In an ascending single-dose pharmacokinetic study of sirolimus in pediatric dialysis patients, no clinically significant association was observed between patient age and absorption of sirolimus from the gastrointestinal tract. However, young pediatric patients (5 to 11 years of age) exhibited significantly greater apparent oral clearances, suggesting that pediatric patients require slightly higher doses than do adults when adjusted for body weight or surface area. Similarly, in studies performed in pediatric renal transplant recipients, the half-life of sirolimus was shorter and the clearance was greater in younger patients. On the other hand, in single-dose pharmacokinetic studies of everolimus, the apparent clearance was reduced in pediatric renal transplant recipients compared with clearance in adults. This reduced clearance was attributed to a smaller apparent volume of distribution in pediatric patients, rather than to a difference in terminal half-life. This suggested that, although the adult 12-hour dosing interval was appropriate for pediatric patients, they would require reduced dosing based on body size compared with adults. In a large trial (N = 719) of sirolimus versus azathioprine in combination with cyclosporine microemulsion and prednisone, 6 pediatric patients (13 to 18 years of age) received sirolimus at 2 mg/d, 3 received sirolimus at 5 mg/d, and 3 received azathioprine. Seven of the nine patients who received sirolimus experienced no rejection episodes. Six infectious episodes occurred in the 6 patients receiving sirolimus at 2 mg/d, 10 episodes occurred in the 3 patients receiving sirolimus at 5 mg/d, and 8 episodes occurred in the 3 patients receiving azathioprine. At 6 months after transplantation, renal function was similar in all 3 groups, although there was a statistically nonsignificant increase in the group receiving sirolimus at 5 mg/d. The mean cholesterol and triglyceride levels were generally comparable in all 3 groups. TOR inhibitors are promising agents for the prevention of graft rejection in pediatric renal transplant recipients, but more pharmacokinetic data are required to assess the optimal dosing regimens in this population. In addition, further data are needed on the efficacy and safety of TOR inhibitors in combination with other agents in pediatric transplantation recipients to best assess the role of TOR inhibition in corticosteroid and/or calcineurin inhibitor-sparing regimens.
Ettenger
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RB
Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles, CA 90095-1752, USA. Rettenger@mednet.ucla.edu
Grimm
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EM
D000293:Adolescent; D000367:Age Factors; D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003524:Cyclosporins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000068338:Everolimus; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007408:Intestinal Absorption; D016030:Kidney Transplantation / Q000276:immunology*; D011241:Prednisone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D000068338:Everolimus; D001379:Azathioprine; D011241:Prednisone; D020123:Sirolimus