Predicting tacrolimus concentrations in children receiving a heart transplant using a population pharmacokinetic model

Abstract

ObjectiveImmunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual’s future concentrations.Design, setting and patientsRetrospective data from 48 children who received tacrolimus as inpatients at Primary Children’s Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant.Outcome measuresData analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset.ResultsConcentrations ranged between 1.5 and 37.7 μg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 μg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (−2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)).ConclusionsThe use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring.

Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients

“…Due to the differences between adults and children, PK parameters, CL/F (9.5 L/h) and V (233 L) were significantly lower than those in this model. 13 In this study, tacrolimus clearance was found to vary with POD and the co-administration of WZ capsules; distribution volume was significantly influenced by BW. POD is a significant covariate with high recognition among various studies.…”

Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients

“…This study developed a population pharmacokinetics (PopPK) model of tacrolimus in pediatric hematopoietic stem cell transplant (HSCT) patients and devised model-guided dosage regimens. One-compartment models with and without lag time have been reported for pediatric patients of different translation types, including lung, kidney, and heart ( Sam et al, 2000 ; Fukudo et al, 2006 ; Guy-Viterbo et al, 2014 ; Lu et al, 2015 ; Rower et al, 2017 ; Andrews et al, 2018 ). In this study, a one-compartment model without lag time was selected.…”

“…Different concomitant medications in immunosuppressant regimens after HSCT transplantation could have an impact on the pharmacokinetics of tacrolimus by affecting the action of CYP3A4 or P-gp, such as voriconazole, itraconazole, and posaconazole ( Cervelli and Russ, 2003 ; Rower et al, 2017 ; Huang et al, 2020 ). In our investigation, concomitant voriconazole use was found to be a major covariate that explains interindividual variability in tacrolimus CL, which is consistent with other PopPK studies.…”

Evaluating risk factors for acute graft versus host disease in pediatric hematopoietic stem cell transplant patients receiving tacrolimus

“…Tacrolimus is a calcineurin inhibitor commonly used for the prevention of acute graft-versus-host disease (aGVHD), defined as GVHD that occurs within 100 days post-transplant (3). To date, there are very limited studies examining the pharmacokinetic (PK) profile of tacrolimus in children post solid organ transplant (4,5). These pharmacokinetic studies have demonstrated significant interpatient variability in drug exposure.…”

“… 3 To date, there are very limited studies examining the pharmacokinetic (PK) profile of tacrolimus in children post solid organ transplant. 4 , 5 These PK studies have demonstrated significant interpatient variability in drug exposure. The oral bioavailability of tacrolimus in children ranges even more widely from 5% to 93%, with a mean bioavailability of 25% in patients who have undergone solid organ transplantation.…”