Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients.
To evaluate the pharmacokinetics of Sirolimus (SRL) and Tacrolimus (TAC) in pediatric transplant recipients. Fifty-one SRL and 55 TAC pharmacokinetic profiles were obtained from 20 male and 14 female recipients of liver alone (LTx, n = 23), small bowel alone, and with liver (SBTx, n = 11). The median age was 13.3 years (range 0.9-23.9). Whole blood concentrations of SRL and TAC were determined by liquid chromatography-mass spectrometry (LC-MS) and microparticulate enzyme immunoassay (MEIA-Abbott Laboratories, IL), respectively. Pharmacokinetic (PK) parameters were derived from noncompartmental model analysis. The half-life was estimated using the data points during the terminal disposition phase and area under the concentration (AUC) time curve was calculated within a dosing interval using the trapezoidal method. The dose of SRL or TAC did not correlate with the corresponding AUCs. Trough concentrations of SRL and TAC correlated well with AUC (r = 0.8544 and 0.8603, respectively). Half-life (h) did not differ significantly between different transplant groups for SRL and TAC (SRL: LTx: 21.2 h, SBTx: 19.3 h; TAC: LTx: 14.1 h, SBTx: 12.7 h). Serial PK analysis with the first measurement within 14 days after transplantation revealed no difference in AUC/dose/BSA for SRL, with time. During this period, SRL half-life increased significantly, from 11.2 +/- 1.0-20.1 +/- 3.1 h (n = 4; p = 0.02). After introduction of SRL, TAC half-life did not change (11.6 +/- 3.9-14.0 +/- 10.4, n = 10, P = 0.52) in all the groups analyzed together. TAC AUC/dose/BSA decreased significantly in LTx and SBTx patients (90.9 +/- 55.3 vs. 48.8 +/- 27.3). Trough concentration measurements provide good estimates of SRL and TAC exposure in pediatric transplant recipients. The short half-life of SRL in children may support twice-daily administration early after liver and small intestinal transplantation. During conversion of subjects from TAC to combined TAC and SRL, aggressive therapeutic drug monitoring must be used to individualize therapy and avoid serous adverse events.
Schubert
Marika
M
Thomas E Starzl Transplantation Institute of the Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Venkataramanan
Raman
R
Holt
David W
DW
Shaw
Leslie M
LM
McGhee
William
W
Reyes
Jorge
J
Webber
Steve
S
Sindhi
Rakesh
R
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D007421:Intestine, Small / Q000276:immunology / Q000637:transplantation*; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D020123:Sirolimus / Q000493:pharmacokinetics*; D016559:Tacrolimus / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus