Dennis M. Fisher, Norma Kellett, Rainer Lenhardt; Pharmacokinetics of an Implanted Osmotic Pump Delivering Sufentanil for the Treatment of Chronic Pain. Anesthesiology 2003;99(4):929-937.
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The plot of the ratio of observed-to-population predicted values was examined. Systematic deviations from the line of unity suggested model misspecification.
The objective function (the objective function, −2 · log likelihood, is equivalent to the residual sum of squares in traditional analyses) was determined for each model. Some comparisons involved two models in which neither model was a smaller version of the other (e.g. , comparing weight-normalized and nonweight-normalized models); in this instance, the model with the smaller objective function was accepted. Some comparisons involved a “larger”versus “smaller” version of the same model (e.g. , 3-vs. 2-compartment models). Using the likelihood ratio test, for each additional parameter (theta ) added to the model, an improvement (decrease) in the objective function of 6.63 units achieves statistical significance with P < 0.01. This conservative P value was selected to prevent type I errors when multiple comparisons (i.e. , a possible role for many covariates) are performed in an exploratory analysis.
Post hoc (individual) values for the pharmacokinetic parameters were plotted against covariates; systematic trends were sought and, if appropriate, incorporated into the model.
For the analysis of the systemic pharmacokinetics of sufentanil, an additional goal was to minimize the terms quantifying interindividual variability.
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