Everolimus in pediatric de nova renal transplant patients.
BACKGROUND
The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period.


METHODS
Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3.


RESULTS
There were 9 boys and 10 girls with a median age of 9.9 (range, 1-16) years. Steady-state pharmacokinetic parameters were as follows (median, range): C(min) (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9-22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53-147) ng x hr/mL; and apparent oral clearance, 10.2 (5.5-15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r=0.66), body surface area (r=0.68), and weight (r=0.67). There were no trends in C(min) or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus C(min) were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine C(min) were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated.


CONCLUSIONS
These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.
Hoyer
Peter F
PF
Department of Pediatric Nephrology, Universitätsklinik Essen, Hufelandstr. 55, D-45122 Essen, Germany. peter.hoyer@uni-essen.de
Ettenger
Robert
R
Kovarik
John M
JM
Webb
Nicholas J A
NJ
Lemire
Jacques
J
Mentser
Mark
M
Mahan
John
J
Loirat
Chantal
C
Niaudet
Patrick
P
VanDamme-Lombaerts
R
R
Offner
Gisela
G
Wehr
Sabine
S
Moeller
Virginia
V
Mayer
Hartmut
H
D000293:Adolescent; D001830:Body Surface Area; D002648:Child; D002675:Child, Preschool; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007223:Infant; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D012044:Regression Analysis; D020123:Sirolimus / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus