Population Pharmacokinetic and Pharmacodynamic Models of Propofol in Healthy Volunteers using NONMEM and Machine Learning Methods

Objectives: The primary objective of this study is to compare model performance of machine learning methods with that of a previous study in which a nonlinear mixed effects model was created using NONMEM (R) for the pharmacokinetic and pharmacodynamic data for propofol. The secondary objective was to evaluate if a pharmacodynamic model describing the relationship between the dose of propofol and bispectral index (BIS) outperform that describing the relationship between a pharmacokinetic model derived-predicted concentrations of propofol and BIS. Methods: Data were collected during a study involving the infusion of propofol into healthy volunteers. Pharmacokinetic and pharmacodynamic models were constructed using artificial neural networks (ANNs), support vector machines (SVMs), and multi-method ensembles and were compared with the nonlinear mixed effects method as implemented by NONMEM (R) . Model performance was assessed by goodness-of-fit statistics, paired t-tests between predicted and observed values for each model and scatterplots. Results: In pharmacokinetic analysis, ensemble I, the mean of ANN and NONMEM (R) predictions, achieved minimal error and the highest correlation coefficient. SVM produced the highest error and the lowest correlation coefficient. In pharmacodynamic analysis, ANN exhibited the best performance. An ANN Model describing the relationship between the dose of propofol and BIS was not inferior to an ANN model describing the relationship between predicted concentrations of propofol derived from an ANN pharmacokinetic model and BIS. Conclusions: In pharmacokinetic analysis, ensemble combined with ANN achieved slightly better performance than NONMEM (R). The relationship between the dose of propofol and BIS can be predicted without considering pharmacokinetics of propofol.