New population pharmacokinetic model that predicts the individual starting dose of tacrolimus following pediatric renal transplantation
L.M. Andrews (1), D.A. Hesselink (2), T. van Gelder (1,2), E.A. Cornelissen (3), S.N. de Wildt (4,6), B.C.P. Koch (1), K. Cransberg (5), B.C.M. de Winter (1)
1Dept. of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands; 2Dept. of Internal Medicine, Erasmus MC; 3Dept. of Pediatric Nephrology, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands 4Dept. of Pharmacology and Toxicology, Radboud University, 5Dept. of Pediatric Nephrology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands, 6 Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands
Objectives: Multiple clinical, demographic and genetic factors affect the pharmacokinetics (PK) of tacrolimus (Tac) in children, yet in daily practice the starting dose is based solely on bodyweight. TDM limits the time a patient is exposed to concentrations outside the target range, but it can take two weeks to reach the target Tac concentration. The aim of this study was to improve the starting dose of tacrolimus after pediatric renal transplantation.
Methods: Clinical, demographic, PK and genetic data were collected for the first six weeks after renal transplantation. All children were treated with basiliximab, Tac, mycophenolic acid and glucocorticoids. Every child had at least one Tac PK profile performed over 4 h. A population PK analysis was conducted using NONMEM (version 7.2, FOCE+I). Demographic, clinical and genetic parameters were evaluated as covariates for all PK parameters containing interpatient variability (IIV). The final model was internally and externally validated using visual predictive checks. Simulations were performed to determine the ideal starting dose.
Results: 46 children with a median age of 9.1 years (range 2.4-17.9) were included. Population PK was best described by a two compartment model. The mean absorption rate was 0.56 h-1 (188% IIV), clearance (CL) was 50.5 L/h (25% IIV), central volume of distribution (Vd) was 206 L (69% IIV) and the peripheral Vd 1520 L (62% IIV). Inter-occasion variability was added to CL (18%) and the peripheral Vd (35%). Allometric scaling was used to adjust for differences in bodyweight. Smaller children had a higher Tac CL. CYP3A5 expressers had a 2 times higher CL. An increase in eGFR from 30 to 90 ml/min resulted in a 19% higher CL, whereas a decrease in hematocrit levels from 0.3 to 0.25 L/L corresponded with a 20% higher Tac CL. Transplantation with a kidney from a deceased donor was associated with a higher Tac CL than living donor. In total, these covariates explained 41% of the variability in CL. No co-medications or time after transplantation were associated with Tac PK. The model was externally validated using an independent dataset of 23 patients.
Conclusions: The tacrolimus weight-normalized starting dose should be higher in patients with a lower bodyweight, who express CYP3A5 and those who receive a kidney from a deceased donor. Using these parameters an individualized dosing regimen has been developed for the initial dosage.
