Population pharmacokinetics of tacrolimus in children who receive cut-downor full liver transplants

Background. The aim of this study was to investigate the population pharmac okinetics of tacrolimus in pediatric liver transplant recipients and to ide ntify factors that may explain pharmacokinetic variability. Methods. Data were collected retrospectively from 35 children who received oral immunosuppressant therapy with tacrolimus. Maximum likelihood estimate s were sought for the typical values of apparent clearance (CL/F) and appar ent volume of distribution (V/F) with the program NONMEM. Factors screened for influence on the pharmacokinetic parameters were weight, age, gender, p ostoperative day, days since commencing tacrolimus therapy, transplant type (whole child liver or cut-down adult liver), liver function tests (bilirub in, alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma -gl utamyl transferase [GGT], alanine aminotransferase [ALT]), creatinine clear ance, hematocrit, corticosteroid dose, and concurrent therapy with metaboli c inducers and inhibitors of tacrolimus. Results. No clear correlation existed between tacrolimus dosage and blood c oncentrations (r(2) =0.003). Transplant type, age, and liver function test values were the most important factors (P <0.01) that influenced the pharma cokinetics of tacrolimus. CL/F estimates were greater in whole liver recipi ents, decreased with increasing patient age and AST values, and increased w ith 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 intersubj ect variability (CV%=110% to 297%) and residual variability (CV%=42%) was o bserved. Conclusions. Pharmacokinetic in-formation obtained in this study may assist physicians in making individualized dosage decisions in regard to tacrolim us in pediatric liver transplant recipients. Children who received a whole child's liver appeared to retain "pediatric" clearance, whereas those who r eceived a cutdown adult liver had "adult" clearances (on average 7-fold les s).