Evaluation of published population pharmacokinetic models to inform tacrolimus dosing in adult heart transplant recipients

Abstract

Background and Aim: Identification of the most appropriate population pharmacokinetic model-based Bayesian estimation is required prior to its implementation in routine clinical practice to inform tacrolimus dosing decisions. This study aimed to determine the predictive performances of relevant population pharmacokinetic models of tacrolimus developed from various solid organ transplant recipient populations in adult heart transplant recipients, stratified based on concomitant azole antifungal use. Concomitant azole antifungal therapy alters tacrolimus pharmacokinetics substantially, necessitating dose adjustments. Methods: Population pharmacokinetic models of tacrolimus were selected (n = 17) for evaluation from a recent systematic review. The models were transcribed and implemented in NONMEM version 7.4.3. Data from 85 heart transplant recipients (2387 tacrolimus concentrations) administered the oral immediate-release formulation of tacrolimus (Prograf) were obtained up to 391 days post-transplant. The performance of each model was evaluated using: (i) prediction-based assessment (bias and imprecision) of the individual predicted tacrolimus concentration of the fourth dosing occasion (MAXEVAL = 0, FOCE-I) from 1-3 prior dosing occasions; and (ii) simulation-based assessment (prediction-corrected visual predictive check). Both assessments were stratified based on concomitant azole antifungal use. Results: Regardless of the number of prior dosing occasions (1-3) and concomitant azole antifungal use, all models demonstrated unacceptable individual predicted tacrolimus concentration of the fourth dosing occasion (n = 152). The predictioncorrected visual predictive check graphics indicated that these models inadequately predicted observed tacrolimus concentrations. Conclusion: All models evaluated were unable to adequately describe tacrolimus pharmacokinetics in adult heart transplant recipients included in this study. Further work is required to describe tacrolimus pharmacokinetics for our heart transplant recipient cohort.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients

“…[12][13][14] From these estimates, an optimal drug dose predicted to achieve target drug concentrations can be ascertained. 15 Implementation of the Bayesian approach to support decision-making in clinical practice has improved the attainment of target tacrolimus concentrations in renal and liver transplant recipients in the early post-transplant period. [16][17][18] Prior to implementing the Bayesian approach in routine clinical practice, a suitable population pharmacokinetic model is needed.…”

“…The Bayesian approach utilizes a population pharmacokinetic model together with patient‐specific information and at least one drug concentration to estimate individual patient pharmacokinetic parameters 12–14 . From these estimates, an optimal drug dose predicted to achieve target drug concentrations can be ascertained 15 . Implementation of the Bayesian approach to support decision‐making in clinical practice has improved the attainment of target tacrolimus concentrations in renal and liver transplant recipients in the early post‐transplant period 16–18 …”

“…External evaluation of existing population pharmacokinetic models using data from the patient population in which it is intended to be used is performed to identify the most suitable model to facilitate dose individualization 19 . Evaluation of a number ( n = 19) of existing tacrolimus models developed from various solid organ transplant recipient populations in heart transplant recipients resulted in poor predictive performances (bias, imprecision and visual predictive checks) 15 . The evaluation also included the only two existing tacrolimus models developed solely using data obtained from heart transplant recipients 20,21 .…”

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

“…This study concluded that the models did not adequately predict tacrolimus dosing for this population and should not be used for clinical dosing prediction. 27 The models evaluated in this study tended to underpredict the actual therapeutic dose. This finding suggests that the CL/F estimates in the models are lower than the actual patient clearance and would have a lower likelihood of resulting in supratherapeutic exposure.…”

“…This study concluded that the models did not adequately predict tacrolimus dosing for this population and should not be used for clinical dosing prediction. 27…”