Predictive Capacity of Population Pharmacokinetic Models for the Tacrolimus Dose Requirements of Pediatric Solid Organ Transplant Recipients

Abstract

Background: Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients.Methods: Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose. Results:The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose. Conclusions:Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.

External assessment and refinement of a population pharmacokinetic model to guide tacrolimus dosing in pediatric heart transplant

“…Descriptions of pediatric heart transplant PK data and/or models in the literature are limited. Furthermore, recent work by Pasternak et al found that tacrolimus models developed in pediatric kidney transplant populations did not extend well to pediatric heart transplant recipients, suggesting a need for organ‐specific PK models 37 . In addition to demonstrating that CYP3A5*1 genotype conferred a greater dose requirement in pediatric heart transplant recipients, Gijsen et al found that the weight‐normalized dose requirement decreased with increasing age 24 .…”

“…Therefore, the finding that the model's plant recipients, suggesting a need for organ-specific PK models. 37 In addition to demonstrating that CYP3A5*1 genotype conferred a greater dose requirement in pediatric heart transplant recipients, 6 The review demonstrates that there exists a wide range of published parameter estimates, covariates, and variability associated with tacrolimus PK.…”

Population pharmacokinetic models of tacrolimus in paediatric solid organ transplant recipients: A systematic review

“…Moreover, evaluating the generalizability of existing models would indicate the necessity for transplant‐specific models. Recently, Pasternak et al 60 . examined the ability of 3 previously published PopPK models 32,37,61 to predict tacrolimus dose requirements for paediatric kidney and heart transplant recipients.…”