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

他克莫司 加药 药代动力学 人口 医学 相伴的 药理学 内科学 移植 环境卫生
作者
Ranita Kirubakaran,David W. Uster,Stefanie Hennig,Jane E. Carland,Richard O. Day,Sebastian G. Wicha,Sophie L. Stocker
出处
期刊:British Journal of Clinical Pharmacology [Wiley]
卷期号:89 (3): 1162-1175 被引量:6
标识
DOI:10.1111/bcp.15566
摘要

Aim Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus‐azole antifungal interaction. Methods Data from heart transplant recipients ( n = 87) administered the oral immediate‐release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building ( n = 1099). A published tacrolimus model was used to inform the estimation of K a , V 2 /F, Q/F and V 3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat‐free mass was implemented as a covariate on CL/F, V 2 /F, V 3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction‐corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion ( n = 87) from one to three prior dosing occasions. Results Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = −44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. Conclusion A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus–azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.
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