In this third and final post about by review of the Phoenix WinNonlin software, I review the newest feature of the software and provide overall thoughts. You can read about the Phoenix platform in Part 1 of my review, and the non-compartmental and single subject analysis in Part 2 of my review. With the exception of WinNonmix which has been discontinued, the WinNonlin software did not include a population pharmacokinetic analysis feature. That is … until now. With the new Phoenix platform, Certara has built a completely new non-linear mixed effects modeling system that seamlessly integrates into the Phoenix platform. This new tool is called Phoenix NLME (short for Non-Linear Mixed Effects), and performs identical analysis to NONMEM, with additional features of an integrated graphical user interface and post-processing.
NLME Workflow Object
As with the other Phoenix tools, everything depends on the NLME workflow object.
The NLME workflow object appears very similar to the non-compartmental analysis and PK model objects. There are 4 main setup items: Main (data), Dosing, Parameters, and Parameter mapping. Each of these function similar to non-compartmental and individual PK analysis as described in Part 2 of my review.
The most important part of any population pharmacokinetic modeling program is the ability to build the appropriate model. In the past, nearly all software packages required learning a unique coding language (usually a version of Fortran) to enter the model using text expressions. Phoenix NLME takes a completely different path and provides three ways to edit models. The first involves built-in models that have closed-form analytical solutions. These built-in models can be selected using drop-down lists from the user interface. The second method is a standard text editor (shown on left below). This editor requires learning a new language but is rather intuitive. The third method, which is my favorite, is the graphical editor (shown on the right below). The graphical editor allows you to draw the desired model using standard compartments and flow arrows.
|Textual Editor||Graphical Editor|
The beauty of the graphical editor is that it allows a user to draw a model then it constructs the needed equations on the fly in the background. These equations are updated in the graphical and textual editor as the model is constructed. This allows the user to define their model using graphical tools without having to worry about the equations needed for the model. But the user can always switch between the text and graphical models to adjust the equations as needed. This graphical editor is available with both NLME and WinNonlin individual PK modeling.
After executing the population model, Phoenix NLME automatically produces tabular, graphical and text output for the user to evaluate the quality of the model fit. The tabular output includes parameter estimates, covariance matrices, residuals, and other model diagnostics. These tabular data can be sent to other Phoenix workflow objects like tables. A variety of plots like the one shown below are automatically produced and can be customized by the user.
The automated output makes model evaluation simple and easy. Following execution of the model the user can directly view the parameter estimates, diagnostic plots, and text output to effectively evaluate the model.
Phoenix has also incorporated some excellent modeling tools to help in the model building effort. First among those tools is the workflow object. Once a model is built and run, the workflow object can be duplicated using “copy/paste”. Then the new workflow object can be modified. This is excellent for testing multiple models within a single project. The second tool is the automated covariate search feature.
As shown above, users can add covariates and select the method of centering, the method of covariate addition (Direction) and the specific parameter to which each covariate should be added. After these selections are made, the automated search will test all combinations of covariates and select the best model using the log-likelihood ratio test. Finally, a workflow object called the “Model Comparer” allows the user to compare model fits.
The user can select several models (top window frame), the items to compare, and the diagnostic plots to compare (lower window frame). Executing this workflow object creates a set of tables with a comparison of the selected parameters, and side-by-side graphical output.
With the new NLME feature in Phoenix, I believe that there are now two comparable options for population pharmacokinetic analysis. Although NONMEM has been the industry standard since the late 1980’s, I believe that the Phoenix interface and powerful modeling tools have put Phoenix NLME in position to gain market share. I enjoy the ability to integrate multiple analysis methods in a single project using the workflow layout. I can move from non-compartmental analysis to population analysis simply by adding a workflow object. The graphical model editor is the new industry standard. Not only is it flexible to allow for differential equations, but the models can be built with the intuitive graphical model builder rather than relying on text entry. Finally, the modeling tools simplify many of the complex modeling tasks such as stepwise covariate addition and model comparisons.
I am impressed with Phoenix WinNonlin/NLME as a complete software package. It is a welcome departure from the historical WinNonlin interface to a modern workspace that allows the analyst to focus on the modeling process rather than the details of the model execution. There is seamless integration of all tools into a single package that is easy to use and powerful. I will likely begin to use Phoenix more often for all of my pharmacokinetic/pharmacodynamic analyses. My only suggestion is to simplify the licensing structure for the product. Although each piece is seamlessly integrated from a software perspective, purchasing the product can be confusing because each feature (e.g. WinNonlin, Connect, NLME, etc.) comes at a different price, and it isn’t always clear which product includes each feature. Future integration of all three would be beneficial to the user.
An evaluation copy of Phoenix was provided by Certara with the WinNonlin, Connect & NLME modules. You can learn more about Phoenix WinNonlin by calling your local Certara representative, or by requesting information from Certara.
One of the most challenging aspects of population pharmacokinetic/pharmacodynamic (PK/PD) modeling is the lack of computing power required to solve complex models in a reasonable time frame to support rapid drug development decisions. The explosion of cloud computing resources has provided access to significant computing power to solve these complex models. However, accessing these cloud computing systems can be complex and confusing. To learn how to accelerate performing NLME modeling, please watch a webinar on this topic.