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

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 prediction-corrected 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.