Review of Phoenix Connect Software Tool

May 6, 2013 By 1 Comment

In this post, I am reviewing the Phoenix® Connect package from Pharsight (A Certara™ Company). Over the past several years, Pharsight has made a significant effort to modernize the pharmacokinetic analysis software tools to aid in the drug development process. While many longtime users of the PCNonlin and WinNonlin software solutions are disappointed with the need to learn a new computer interface, I liken this change similar to the move from text entry computers (e.g. DOS) to the windows-based platforms we now use (e.g. Windows, Mac OSX). You can still find people who love command-line computing; however the vast majority of users are comfortable and even more efficient with the graphical user interfaces we now see on computers and other electronic devices.

The Phoenix platform consists of modular packages that fit together on the Phoenix whiteboard to provide an integrated solution for pharmacokinetic and pharmacodynamic analysis.

Phoenix Platform

Phoenix Platform

These software packages, each with a different purpose, fit together interchangeably, similar to the toy Lego’s. This review focuses on the Phoenix Connect product which is displayed as a Data Management tool; however it actually provides connectivity to a myriad of other external tools. I prefer to think of Phoenix Connect as the tool that connects items within Phoenix to the outside world. Phoenix Connect has 3 primary functions, which I will review in order:

  1. Connecting Phoenix with data sources
  2. Integration of external analysis tools into Phoenix workflows
  3. Exporting results for reporting

Connecting Phoenix with data sources

Pharmacokinetic analysis is one part of data analysis in a study. As such, data flows from one source to another with the final location a report or regulatory document. The Phoenix Connect tool provides seamless integration to connect incoming demographics and concentration data with pharmacokinetic analysis procedures. Phoenix Connect provides methods to connect to a variety of external data sources. One of those sources is the Pharsight Knowledgebase Server (PKS), a proprietary database for PK and PD analyses. Phoenix Connect also provides flexibility by allowing import of SAS transport files in SDTM formats, or other external database structures (e.g. Oracle’s ODBC).

While connectivity to external data sources is important, Phoenix amplifies this valuable feature of Phoenix Connect by allowing for creation of templates and data links to automate data import. This allows a user to set up a pharmacokinetic analysis procedure (e.g. handling of BLQ values, non-compartmental analysis, concentration-time plots, data summarization, etc.) that can be repeated by simply connecting to new data sources.

Integration of external analysis tools

Many users think of Phoenix as an updated version of Pharsight’s WinNonlin product. But Phoenix is really a whiteboard platform that can be used with a large number of analysis tools. Phoenix Connect permits analysis with NONMEM, R, S-Plus, SAS, and many other analytical tools. There are competing tools that Pharsight sells (e.g. Phoenix WinNonlin, and Phoenix NLME); however, the Phoenix platform can be used to conduct native analyses with other tools. With Phoenix Connect, the user can add a NONMEM object that includes the dataset, control stream, and all output files. The resulting output files can then be used in other Phoenix objects (tables, plots, etc.) including integrated R-scripts. Phoenix Connect allows the user to organize and standardize pharmacometric analysis. Instead of a myriad of files and directories, all pharmacometric files are consolidated in a single Phoenix project file.

NONMEM Setup

NONMEM setup

NONMEM Output

NONMEM Output

NONMEM Plot

NONMEM Plot

This feature of Phoenix Connect allows for consolidation and harmonization of all pharmacokinetic and pharmacometric analyses using the Phoenix platform, while retaining the value of multiple analysis tools (e.g. WinNonlin, NONMEM, R, etc.). Analyses can be performed using the native environment, yet the advantages of Phoenix can be leveraged with any of these tools. Using Phoenix Connect with external analysis tools also provides an increased level of quality control that can improve compliance with regulations and company standard operating procedures.

Exporting results for reporting

Phoenix Connect also provides a reporter tool that can be used to export results for incorporation into study reports. This feature completes the connection of Phoenix from data to results. The reporter tool allows you to select tables, figures, or text (called “listings” in the Reporter object) from your workflow and output them into a Microsoft Word document using context-sensitive table/figure/listing titles. The reporter object functions like all other Phoenix objects in that it takes inputs (tables, figures and text) and operates on it to produce output (MS Word file).

This new Reporter object can be used to compile tables and figures for study reports easily and quickly. For example, let’s take a bioequivalence clinical study (2-period 2-way crossover study). Standard figures include individual concentration-time profiles, mean concentration-time profiles for each formulation, and dot plots comparing Cmax and AUC across formulations. Standard tables include a listing of concentration-time data by subject, listing of individual PK parameter estimates, mean concentration-time data by formulation, mean PK parameter estimates by formulation, and a statistical comparison of Cmax and AUC across formulations. All of these tables and figures can be produced using Phoenix objects (table objects and plot objects, respectively). Instead of exporting each one independently, these objects can be fed into a Reporter object with context-sensitive information (e.g. analyte name, formulation, period, subject ID, etc.) that can be included in the title of the table or figure. These separate objects can then be exported together into a Microsoft Word document that can be saved and directly imported into a clinical study report.

Reporter Setup

Reporter Setup

 

Reporter Output

Reporter Output

If the data is updated, then the Reporter object, like any other Phoenix object, will turn pink to notify you that it is not current with the preceding objects. You can quickly refresh the workflow and update the output document to reflect the changes. This new Reporter object can be used within templates to standardize output for different studies and reports.

The new Reporter tool is an exciting advancement for the Phoenix platform. While Phoenix has been an excellent analysis platform, it always lacked a quality method for exporting information in an easy and useful manner. Individual file exports were time consuming, and could not be tracked within the workflow. In addition, the output was simply a data dump rather than a series of organized outputs that are report-ready. By adding the ability to customize titles and footers, the Reporter tool allows Phoenix to fully execute analyses from input data to final output (tables, figures, listings) for pharmacokinetic and pharmacodynamic analyses.

Overall impression and recommendations for the future

The updates to the Phoenix Connect product have made it an indispensable part of the Phoenix experience. The data connections provide access to a wide range of data sources. As companies begin to standardize on SDTM data formats, the data connection tool will become increasingly important instead of requiring a separate PK analysis dataset to be created by a SAS programmer. The ability to execute 3rd party software within Phoenix is the hidden gem of the Phoenix Connect product. This permits incorporation of tools into a regulatory compliant workflow that can be controlled in a validated environment. It simplifies the collection of output, and clearly identifies whether the results are current by color coding (white for current, pink for not current). Using Phoenix to manage your pharmacometrics work may soon become the standard for NONMEM control file management in the future. Additional tools such as custom R or S-Plus scripts or even custom SAS code allow the pharmacokinetic scientist to execute programs independently in a way that permanently links the analysis to the inputs and outputs. Finally, the new reporter tool is a first step to providing quality, report-ready output for inclusion in study reports. The reporter tool’s context-sensitive titles and footnotes are simple, useful, and easy to create. Like other objects, the reporter confirms that the output is current by the same color coding (white and pink) used in all other Phoenix objects. Future additions of reporter outputs to PowerPoint files, font selections for titles, and footnote locations will further refine the reporter tool to make it even more useful.

I highly recommend using the Phoenix Connect tool in your standard pharmacokinetic analysis workflow. Also, addition of this tool turns Phoenix into a pharmacometrics platform, even if you use NONMEM exclusively for your nonlinear mixed-effects modeling work. You can learn more about Phoenix Connect at the Pharsight website (http://www.certara.com/products/pkpd/phx-connect).

Filed Under: NONMEM, Phoenix, Software, WinNonlin Tagged With: ,

Changing column names and units in Phoenix WinNonlin

December 22, 2012 By 2 Comments

One of the most common tasks when working with data in Phoenix WinNonlin is to change the column titles or units. In many software packages that consists of clicking on the data spreadsheet and re-typing the new information; however, with Phoenix, you have to take a few additional steps. Here’s some quick tips on how to change column names and units:

Select the original dataset and send it to a Data Wizard object. You will make all of you changes within this Data Wizard object.

In the Data Wizard object, select the “Properties” under the Action menu.

Properties

You will then see a screen with your existing column titles and units. In this example, there are 2 columns: “TimeofSample” and “Result”. I would like to change these to “Time” with units of hours, and “Conc” with units of ng/mL. This can be done in a single quick Data Wizard step.

Start

Select the “Old Column” that you would like to change in the box. Then the properties boxes on the right will change from grey to black. Just enter a new column name and the new units in the boxes provided. You can use the Unit Builder if necessary to help you. After you complete your changes, press the “Enter” or “Return” key. You will then get a response box like this:

Convert units

In this case we are setting the units for the first time, so we can click “No”. If we were converting the units from ng/mL to mg/mL, then we would click “Yes” to convert units. After you change all of the columns and units, click the “Execute Step” button on the left site of the dialog. This will execute the Data Wizard step and create the new dataset with the updated column titles and units:

Original
Original
Modified
Results

That’s how you change column names and units in Phoenix WinNonlin. A little more complex than in some other spreadsheet software, but not too difficult.

 

Filed Under: Software, WinNonlin Tagged With: ,

Phoenix NLME Software Review – Part 3

May 26, 2011 By 3 Comments

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 noncompartmental 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, Pharsight has built a completely new non-linear mixed effects modeling system that seamlessly integrates into the Phoenix platform. This new tool is called 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 (shown below, click to enlarge).

NLME Workflow Object

NLME Workflow Object

The NLME workflow object appears very similar to the noncompartmental analysis and PK model objects. There are 4 main setup items: Main (data), Dosing, Parameters, and Parameter mapping. Each of these function similar to noncompartmental and individual PK analysis as described in Part 2 of my review.

Model Editor

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 3 ways to edit models. The first involves built-in models that have closed-form analytical solutions. These built-in models can be selected using dropdown 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
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 contructed. 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.

Output

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.

Output plot

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.

Modeling tools

Phoenix has also incorporated some excellent modeling tools to help in the model building effort. First among those tools is the worflow 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. CovariateAs 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. Model ComparerThe 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.

Overall

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 noncompartmental 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 Pharsight with the WinNonlin, Connect & NLME modules. You can learn more about Phoenix WinNonlin by visiting the vendor’s website, by calling your local Pharsight representative, or by requesting information from Pharsight.

Filed Under: pharmacokinetics, Software, WinNonlin Tagged With: , ,

Phoenix WinNonlin Software Review – Part 2

May 18, 2011 By 18 Comments

Part 2 of the WinNonlin review will cover the noncompartmental and PK modeling functions of Phoenix WinNonlin. To many people, these 2 features have defined WinNonlin for many years. And the updated software does not disappoint with significant improvements to the functionality, ease of use, automated graphics, and other features.

As I discussed in Part 1 of my review, the new Phoenix platform allows integration of data and analysis methods. The “WinNonlin” feature includes the noncompartmental analysis and individual PK modeling features. These features were the basis for the previous versions of standalone WinNonlin versions 3, 4, and 5. Thus using the term “Phoenix WinNonlin” signifies the use of the new Phoenix platform to execute analyses with WinNonlin. This confusing nomenclature for the products is not helpful to the user, but it can be fixed very easily.

Noncompartmental Analysis

The noncompartmental analysis workflow object is shown here.

Noncompartmental Workflow Setup

NCA Workflow Setup

Within this workflow object you can select the options for the noncompartmental analysis, including the type of model, if sparse data is included, the AUC calculation method, and the terminal slope method. One change in the noncompartmental analysis engine from previous versions of WinNonlin is that Cmax is no longer included in the terminal slope calculation.

In addition to the analysis options, the concentration-time data to be used is identified in the “Main” item, dosing information can be imported from a dataset or by manual entry, slopes can be selected by the WinNonlin algorithm (maximize adjusted r2) or manually, partial areas can be defined, units can be specified, and parameter names can be selected or modified. A new feature of the noncompartmental engine is the ability to define a therapeutic response window. Lower and upper bounds can be specified by treatment or by subject. These bounds then appear on plots of concentration-time data. This feature is great for identifying either efficacy levels or toxicity margins.

After all of the input options have been selected, the model can be executed to produce the desired output. The results are presented in a set of tables under the results option. These include parameter estimates, exclusions, dosing information, and various settings. An example of the parameters table, in CDISC-like format is shown below:

Noncompartmental parameter output

NCA Parameter Output

Each of the output worksheets can be sent to other Phoenix objects such as tables or plots. If standard tables and plots templates have been created prior to analysis, the delivery of report-ready tables and graphics can be instantaneous. Although it appears that little has changed with the NCA engine, there have been a few modifications that simplify data analysis. First, the number of models has been reduced to 3 basic model types (plasma, urine, drug effect) with separate selections for the dosing input profile, and steady-state settings. The second improvement is the improved plotting engine which provides report-ready graphics without having to leave the application. And finally, the dosing input is simplified and can be automatically populated using study design features.

PK Models

The pharmacokinetic model workflow object is shown here.

PK Model Workflow Object

Pharmacokinetic Model Workflow Object

The model can be selected by double-clicking the “PK Model” workflow object icon shown at the top of the image to the right. This pulls up the different models that can be selected. It also permits selection of weighting options, the ability to select initial estimates, and minimization options.

The model requires 4 inputs: The study data (time and concentration), dosing information, initial parameter estimates, and units. The Main input includes the concentration-time data and any unique identifiers (e.g. subject ID, sex, weight, etc.). The Dosing input can be entered by the user or added from a data file. The initial estimates are entered by the user, and the units for both input and output parameters can be adjusted as needed.

After the workflow is set, the user can execute the model by running the workflow. The results include standard modeling output such as parameter estimates, residuals, model diagnostics, variance estimates and predicted values. All of these results are presented in worksheets and can be converted to report-ready tables using the Table workflow object. The user also receives the settings and model fits in the text output. Finally, diagnostic plots are automatically produced using the new plotting engine. These plots are fully customizable and can include data from multiple datasets. One example of these plots is shown here:

PK Model Fit

PK Model Fit Plot

Any of the results files can be sent to a plot, table, or other workflow object. This powerful feature provides easy communication of modeling results for study reports or even presentations. This workflow makes individual model fits simple and easy. And since these PK models can be integrated with other objects, you could take mean concentration-time output from a large dataset and send it to a PK Model object to generate initial estimates of the PK model before embarking on a population analysis.

Overall

For many users of WinNonlin versions 3 through 5, the new Phoenix WinNonlin interface presented an unexpected learning curve; however, I believe the improvements are well worth the time required to relearn how to interact with the software. Minor modifications have been made in the noncompartmental and PK modeling features of WinNonlin. The modifications (mentioned above) are nice, but for me, there are 2 key features of the new software that make my life easier. First, the graphics rival those produced within R or SigmaPlot with little or no effort to learn a different software package. These plots can be linked to output so that they are automatically updated if the output changes, and the whole package (analysis and plots) can be set up as a template for repetitive analyses. The second feature is the ability to “send” a result object (e.g. parameter worksheet) to another workflow object. Before Phoenix WinNonlin, I would export output from WinNonlin into another application to create tables and figures. Now, I can simply send the results from either my NCA or PK Model output to a table or plot workflow object within the Phoenix platform.

Overall, the noncompartmental and PK modeling features of WinNonlin are of high quality and include the desired features. Operation is simple and straightforward. And added features such as the improved plotting engine and the workflow interactivity have created a single platform for pharmacokinetic data analysis and reporting.

An evaluation copy of Phoenix was provided by Pharsight with the WinNonlin, Connect & NLME modules. You can learn more about Phoenix WinNonlin by visiting the vendor’s website, by calling yourlocal Pharsight representative, or by requesting information from Pharsight.

Filed Under: pharmacokinetics, Software, WinNonlin Tagged With: ,

WinNonlin Software Review – Part 1

May 4, 2011 By 7 Comments

WinNonlin by Pharsight has been a fixture in pharmacokinetic analysis software for over 20 years. While it has been known as a tool for noncompartmental analysis and model-based analysis of single subject data, the new Phoenix WinNonlin creates an entirely new platform for pharmacokinetic and pharmacodynamic analysis. Similar to my review of NONMEM, I will be evaluating features and usability of the Phoenix WinNonlin software from a user’s perspective.

Part 1 will review the Phoenix platform and integration with other tools. Part 2 will review the noncompartmental and individual pharmacokinetic model fitting tools. Finally Part 3 will review the new nonlinear mixed effects module (NLME).

The installation of Phoenix was simple and easy. A standard Windows installation program was used with the default options on computers with Windows Vista, Windows 7, and a Mac running Windows Vista through a Virtual Machine. WinNonlin is not natively supported on operating systems other than Windows (e.g. Linux, Mac OS X, and UNIX).

The new Phoenix platform is best described with a picture (Click image to enlarge).

Phoenix Workflow

Phoenix Workflow

The newly designed interface has a centerpiece called the “workflow”. The left side of the image shows the object browser. This is where you have a list of all the objects in your file, and it is organized much like a set of nested folders. Users who are familiar with the Windows File Explorer or the SPlus statistical package will be immediately comfortable with the object browser. The right side of the image shows the workflow space. Within this white space you can place objects and then cause them to interact with one another. The orange box titled “External Sources” is a collection of data sets from external sources. Those data sets act as the input for 5 different noncompartmental analysis (NCA) objects that each have their own properties and output. The NCA in the lower left of the image is then the source of a summary statistics worksheet titled “Descriptive Stats”.

The types of objects available to use in Phoenix include: worksheets, plots, NCA, nonlinear modeling, nonlinear mixed effects modeling, in vitro-in vivo correlation tools, tables, NONMEM, SAS shell, SigmaPlot shell, SPlus script, R scripts, and other workflow objects. Each object in the workflow (or box on the white space) has its own inputs, results, and outputs. Each of these outputs can then be directed to become the input of another object (e.g. a set of final PK parameters from an NCA object can be sent to a table object). These workflow connections are illustrated by arrows and are saved in the single Phoenix project file. This allows a single workflow to be used as a template. For example, you could set up a template workflow for a drug-drug interaction study that includes the following:

  • NCA analysis for Drug 1
  • NCA analysis for Drug 2
  • Summary statistics worksheet for Drug 1
  • Summary statistics worksheet for Drug 2
  • Statistical comparison of drug-drug interaction
  • Tables for summary statistics of Drug 1, Drug 2, and drug-drug interaction
  • Plots with individual and mean concentration-time data

This workflow could be saved as a Phoenix template file and then when a new study is conducted the concentration-time data can be added to the workflow, linked to the NCA analyses and a single button click will perform all analyses, calculate summary statistics, and produce the desired tables and figures. This ability to automate can revolutionize traditional pharmacokinetic analysis to simplify the work, standardize output, and allow for faster data analysis.

A new feature with Phoenix is is the ability to incorporate different analysis types on a single workflow. A single workflow can contain NCA, individual nonlinear models, and nonlinear mixed effects or population models. No need to switch back and forth between multiple model files for different analyses on a single set of data! You can conduct your NCA for initial estimates, along with 1- and 2-compartment model fits on the same workflow.

In addition to the workflow feature, Phoenix integrates well with other software packages such as NONMEM, SAS, R, SPlus, and ODBC-compliant databases like Watson LIMS. This integration is achieved through the Phoenix Connect module that allows seamless transfer of Phoenix output to selected software programs, and then the ability to receive output from those same programs. An example of this is the export of AUC values to SAS for statistical analysis followed by the import of the bioequivalence summary statistics into Phoenix for inclusion in a table object. This allows the Phoenix workflow to control data analysis procedures from beginning to end, while allowing a user to interact with their preferred software solution.

Overall, the new workflow layout and design is a significant advance in pharmacokinetic software. And although the new Phoenix user interface is a departure from the previous one, the flexibility and power of the new workflow will create a great opportunity for users to streamline their work processes and simplify data analysis.

More to come in Part 2 (NCA and individual model fitting) and Part 3 (NLME) of my review of Phoenix WinNonlin.

An evaluation copy of Phoenix was provided by Pharsight with the WinNonlin, Connect & NLME modules. You can learn more about Phoenix WinNonlin by visiting the vendor’s website, by calling your local Pharsight representative, or by requesting information from Pharsight.

Filed Under: pharmacodynamics, pharmacokinetics, Software, WinNonlin Tagged With: , , , ,