Population pharmacokinetics of tacrolimus in children who receive cut-down or full liver transplants.
BACKGROUND
The aim of this study was to investigate the population pharmacokinetics of tacrolimus in pediatric liver transplant recipients and to identify factors that may explain pharmacokinetic variability.


METHODS
Data were collected retrospectively from 35 children who received oral immunosuppressant therapy with tacrolimus. Maximum likelihood estimates were sought for the typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) with the program NONMEM. Factors screened for influence on the pharmacokinetic parameters were weight, age, gender, postoperative day, days since commencing tacrolimus therapy, transplant type (whole child liver or cut-down adult liver), liver function tests (bilirubin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], alanine aminotransferase [ALT]), creatinine clearance, hematocrit, corticosteroid dose, and concurrent therapy with metabolic inducers and inhibitors of tacrolimus.


RESULTS
No clear correlation existed between tacrolimus dosage and blood concentrations (r2=0.003). Transplant type, age, and liver function test values were the most important factors (P<0.01) that influenced the pharmacokinetics of tacrolimus. CL/F estimates were greater in whole liver recipients, decreased with increasing patient age and AST values, and increased with increasing GGT values. Average parameter estimates were CL/F=5.75 L/h (cut-down liver), CL/F=44 L/h (whole liver), and V/F=617 L. Marked intersubject variability (CV%=110% to 297%) and residual variability (CV%=42%) was observed.


CONCLUSIONS
Pharmacokinetic information obtained in this study may assist physicians in making individualized dosage decisions in regard to tacrolimus in pediatric liver transplant recipients. Children who received a whole child's liver appeared to retain "pediatric" clearance, whereas those who received a cut-down adult liver had "adult" clearances (on average 7-fold less).
Staatz
C E
CE
School of Pharmacy, University of Queensland, Brisbane, Queensland 4072, Australia. s.tett@pharmacy.uq.edu.au.
Taylor
P J
PJ
Lynch
S V
SV
Willis
C
C
Charles
B G
BG
Tett
S E
SE
D000293:Adolescent; D000375:Aging / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016903:Drug Monitoring; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000201:enzymology / Q000503:physiopathology; D016031:Liver Transplantation / Q000379:methods*; D008962:Models, Theoretical; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D007166:Immunosuppressive Agents; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D016559:Tacrolimus