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External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients
Author(s) -
Zhao ChenYan,
Jiao Zheng,
Mao JunJun,
Qiu XiaoYan
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12830
Subject(s) - predictability , population , bayesian probability , extrapolation , computer science , predictive modelling , econometrics , statistics , medicine , mathematics , machine learning , environmental health
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.