Article date: May 2016
By: Chen‐Yan Zhao, Zheng Jiao, Jun‐Jun Mao, Xiao‐Yan Qiu in Volume 81, Issue 5, pages 891-907
Aim
Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors.
Methods
Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction‐based prediction error (PE%), (2) simulation‐based prediction‐ and variability‐corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated.
Results
Sixteen published models were evaluated. In prediction‐based diagnostics, the PE% within ±30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation‐based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2–3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non‐linear kinetics were used.
Conclusions
The published models were unsatisfactory in prediction‐ and simulation‐based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non‐linear pharmacokinetics in modelling might be a promising approach to improving model predictability.
DOI: 10.1111/bcp.12830
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