Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004

Abstract

Model evaluation is an important issue in population analyses. We aimed to perform a systematic review of all population pharmacokinetic and/or pharmacodynamic analyses published between 2002 and 2004 to survey the current methods used to evaluate models and to assess whether those models were adequately evaluated. We selected 324 articles in MEDLINE using defined key words and built a data abstraction form composed of a checklist of items to extract the relevant information from these articles with respect to model evaluation. In the data abstraction form, evaluation methods were divided into three subsections: basic internal methods (goodness-of-fit [GOF] plots, uncertainty in parameter estimates and model sensitivity), advanced internal methods (data splitting, resampling techniques and Monte Carlo simulations) and external model evaluation. Basic internal evaluation was the most frequently described method in the reports: 65% of the models involved GOF evaluation. Standard errors or confidence intervals were reported for 50% of fixed effects but only for 22% of random effects. Advanced internal methods were used in approximately 25% of models: data splitting was more often used than bootstrap and cross-validation; simulations were used in 6% of models to evaluate models by a visual predictive check or by a posterior predictive check. External evaluation was performed in only 7% of models. Using the subjective synthesis of model evaluation for each article, we judged the models to be adequately evaluated in 28% of pharmacokinetic models and 26% of pharmacodynamic models. Basic internal evaluation was preferred to more advanced methods, probably because the former is performed easily with most software. We also noticed that when the aim of modelling was predictive, advanced internal methods or more stringent methods were more often used.

Figure 1

Screening of the articles selected in Pubmed using exclusion criteria.

Figure 2

Different types of evaluation (none, basic internal only, advanced internal, or external) per date, applied to PK models (left panel) and PD models (right panel).

Figure 3

Answers to the subjective synthesis questions about PK models (left panel) and PD models (right panel) evaluation. The subjective questions were: (1) “Was there an attempt to evaluate the model?”; (2) “Was the choice of the metrics appropriate?”; (3) “Was the model evaluated?”.