Getting Started Guide

Phoenix WinNonlin 6.3 Phoenix Connect 1.3 Phoenix NLME 1.2

Phoenix
Phoenix WinNonlin 6.3, Connect 1.3, and NLME 1.2 copyright 2005-2012, Certara, L.P. All rights reserved. This software and the accompanying documentation are owned by Certara, L.P. Pharsight is authorized to distribute and sublicense the material contained herein with the express written permission of Certara, L.P. The software and the accompanying documentation may be used only as authorized in the license agreement controlling such use. No part of this software or the accompanying documentation may be reproduced, transmitted, or translated, in any form or by any means, electronic, mechanical, manual, optical, or otherwise, except as expressly provided by the license agreement or with the prior written permission of Certara, L.P. This product may contain the following software that is provided to Certara, L.P. under license: Actuate Formula One copyright 1993-2003 Actuate Corporation. All rights reserved. Dundas Chart for ASP.NET enterprise edition 5.5.1.1700 (with custom code changes) copyright 2009 Dundas Data Visualization and others. All rights reserved. Tab Pro ActiveX 2.0.0.45 copyright 1996-1998, FarPoint Technologies, Inc. All rights reserved. Sentinel RMS 8.1.1 copyright 2006 SafeNet, Inc. All rights reserved. Microsoft XML Parser version 3.0 copyright 1998-2005 Microsoft Corporation. All rights reserved. Certara, L.P. has agreement with the following software to use and redistribute licenses: Syncfusion Essential Studio Enterprise 6.302.0.30 copyright 2001-2009 Syncfusion Inc. All rights reserved. Minimal Gnu for Windows (MinGW, http://mingw.org/), copyright 2007 Free Software Foundation, Inc. This product may also contain the following royalty free software: DotNetbar 1.0.0.24030 (with custom code changes) copyright 1996-2009 DevComponents LLC. All rights reserved. Xceed zip Library 2.0.116.0 copyright 2009 Xceed Software Inc. All rights reserved. IMSL copyright 1970-2008 Visual Numerics, Inc. All rights reserved. Information in the documentation is subject to change without notice and does not represent a commitment on the part of Pharsight Corporation or Certara, L.P. The documentation contains information proprietary to Certara, L.P. and is for use by Pharsight Corporation, and its affiliates' and designates' customers only. Use of the information contained in the documentation for any purpose other than that for which it is intended is not authorized. NONE OF PHARSIGHT CORPORATION, CERTARA, L.P., NOR ANY OF THE CONTRIBUTORS TO THIS DOCUMENT MAKES ANY REPRESENTATION OR WARRANTY, NOR SHALL ANY WARRANTY BE IMPLIED, AS TO THE COMPLETENESS, ACCURACY, OR USEFULNESS OF THE INFORMATION CONTAINED IN THIS DOCUMENT, NOR DO
THEY ASSUME ANY RESPONSIBILITY FOR LIABILITY OR DAMAGE OF ANY KIND WHICH MAY RESULT FROM THE USE OF SUCH INFORMATION.

Destination Control Statement

All technical data contained in the documentation are subject to the export control laws of the United States of America. Disclosure to nationals of other countries may violate such laws. It is the reader's responsibility to determine the applicable regulations and to comply with them.

United States Government Rights

This software and accompanying documentation constitute commercial computer software and commercial computer software documentation as such terms are used in 48 CFR 12.212 (Sept 1995). United States Government end users acquire the Software under the following terms: (i) for acquisition by or on behalf of civilian agencies, consistent with the policy set forth in 48 CFR 12.212 (Sept 1995); or (ii) for acquisition by or on behalf of units of the Department of Defense, consistent with the policies set forth in 48 CFR 227.7202-1 (June 1995) and 227.7202-3 (June 1995). The manufacturer is Pharsight Corporation, 1699 South Hanley Road, Suite 200, St. Louis, MO 63144.

Trademarks
AutoPilot, Drug Model Explorer (DMX), Pharsight Knowledgebase Server (PKS), PKS Reporter, Pharsight, Phoenix, Phoenix Connect, Phoenix NLME, Phoenix WinNonlin, IVIVC Toolkit, Trial Simulator, WinNonlin, and WinNonMix are trademarks or registered trademarks of Certara, L.P. and are licensed to Pharsight Corporation as provided above. NONMEM is a registered trademark of ICON Development Solutions. SPLUS is a registered trademark of Insightful Corporation. SAS and all other SAS Institute Inc. product or ser-

vice names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries. Sentinel RMS is a trademark of SafeNet, Inc. Microsoft, MS, the Internet Explorer logo, MS-DOS, the Office logo, Microsoft Word, Microsoft Excel, Microsoft PowerPoint, Windows, Windows 2000, Windows XP, Windows Vista, the Windows logo, the Windows Start logo, and the XL design (the Microsoft Excel logo) are trademarks or registered trademarks of Microsoft Corporation. Pentium and Pentium III are trademarks or registered trademarks of Intel Corporation. Adobe, Acrobat, Acrobat Reader, and the Adobe PDF logo are registered trademarks of Adobe Systems Incorporated. All other brand or product names mentioned in this documentation are trademarks or registered trademarks of their respective companies or organizations.

Additional third party software acknowledgements

Software for Locally-Weighted Regression The authors of this software are Cleveland, Grosse, and Shyu. Copyright 1989, 1992 by AT&T. Permission to use, copy, modify, and distribute this software for any purpose without fee is hereby granted, provided that this entire notice is included in all copies of any software which is or includes a copy or modification of this software and in all copies of the supporting documentation for such software. This software is being provided as is, without any express or implied warranty. In particular, neither the authors nor AT&T make any representation or warranty or any kind concerning the merchantability of this software or its fitness for any particular purpose. LAPACK Copyright 1992-2007 The University of Tennessee. All rights reserved. Redistribution and use in source and binary forms, with or without modification, are permitted provided that the following conditions are met: Redistributions of source code must retain the above copyright notice, this list of conditions and the following disclaimer. Redistributions in binary form must reproduce the above copyright notice, this list of conditions and the following disclaimer listed in this license in the documentation and/or other materials provided with the distribution. Neither the name of the copyright holders nor the names of its contributors may be used to endorse or promote products derived from this software without specific prior written permission. This software is provided by the copyright holders and contributors as is and any express or implied warranties, including, but not limited to, the implied warranties of merchantability and fitness for a particular purpose are disclaimed. In no event shall the copyright owner or contributors be liable for any direct, indirect, incidental, special, exemplary, or consequential damages (including, but not limited to, procurement of substitute goods or services; loss of use, data, or profits; or business interruption) however caused and on any theory of liability, whether in contract, strict liability, or tort (including negligence or otherwise) arising in any way out of the use of this software, even if advised of the possibility of such damage. NLog Copyright 2004-2006 Jaroslaw Kowalski <[email protected]>. All rights reserved. Redistribution and use in source and binary forms, with or without modification, are permitted provided that the following conditions are met: Redistributions of source code must retain the above copyright notice, this list of conditions and the following disclaimer. Redistributions in binary form must reproduce the above copyright notice, this list of conditions and the following disclaimer in the documentation and/or other materials provided with the distribution.

Neither the name of Jaroslaw Kowalski nor the names of its contributors may be used to endorse or promote products derived from this software without specific prior written permission. This software is provided by the copyright holders and contributors as is and any express or implied warranties, including, but not limited to, the implied warranties of merchantability and fitness for a particular purpose are disclaimed. In no event shall the copyright owner or contributors be liable for any direct, indirect, incidental, special, exemplary, or consequential damages (including, but not limited to, procurement of substitute goods or services; loss of use, data, or profits; or business interruption) however caused and on any theory of liability, whether in contract, strict liability, or tort (including negligence or otherwise) arising in any way out of the use of this software, even if advised of the possibility of such damage.

Pharsight Corporation 1699 S. Hanley Road, St. Louis, MO 63144 USA Telephone: +1-919-859-6868 Fax: +1-919-859-6871 www.pharsight.com [email protected]

Contents

Chapter 1

Installation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Pharsight contact information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 System and hardware requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Installing Phoenix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Modifying, updating, or removing a Phoenix installation . . . . . . . . . . . . . . 12 Phoenix 64 bit Versus 32 bit Version . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Functional differences between 32 bit and 64 bit. . . . . . . . . . . . . . . . . . 13 Compatibility Exceptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Job Management Service (JMS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Configuring Phoenix for international use . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Opening TCP ports for MPICH2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Licensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 Phoenix Licensing Service . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 License key code types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Product and authorization codes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Plug-in licenses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 WinNonlin 5.3 license holders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 License Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 License Server Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Testing the Installation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29 Start Phoenix and create a new project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Confirm license installation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Confirm plug-in startup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Import a data set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Create a plot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Create a table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
v

Chapter 2

Chapter 3

Phoenix Getting Started Guide

Confirm model functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Noncompartmental analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Pharmacokinetic modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Bioequivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Chapter 4 Installation test for Pharsight Phoenix NLME . . . . . . . . . . . . . .55 Start Phoenix and create a project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Population modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

vi

Chapter 1

Installation
Installing the Phoenix Platform

The Getting Started Guide contains installation and licensing instructions for Phoenix WinNonlin, Connect, NLME, and the IVIVC Toolkit. The generic term Phoenix is used in this guide to simplify terminology. This chapter contains the following topics: Pharsight contact information on page 1 System and hardware requirements on page 2 Installing Phoenix on page 5 Modifying, updating, or removing a Phoenix installation on page 12 Configuring Phoenix for international use on page 14 Opening TCP ports for MPICH2 on page 15

Pharsight contact information

Consult the documentation to address questions. If further assistance is needed, then contact Pharsight customer support.

Customer support Email Web Phone Fax Post [email protected] www.pharsight.com/support/support_home.php +1-919-852-4620 +1-919-859-6871 Pharsight Corporation 5520 Dillard Drive, Suite 260 Cary, North Carolina 27518

Phoenix Getting Started Guide Contact Pharsight sales for purchases, license renewals, and product upgrades.

Sales Email Phone Fax [email protected] +1-888-708-7444 (US only) +1-919-852-4685 (International) +1-973-828-0273

For licensing issues, including sales and technical support, use the following contact information.

Licensing sales and support Email [email protected]

System and hardware requirements

Phoenix is a software platform built on the Microsoft .NET 2.0 framework. It uses the MinGW (Minimalist GNU for Windows) compiler to create PML (Phoenix Modeling Language) models. Phoenix also uses MPICH2 to allow usage of multiple CPUs and CPU cores. All software prerequisites needed to use basic Phoenix functions are included in the Phoenix installation file. Extended Phoenix functions have additional software requirements.

Required software
Microsoft Windows Installer 3.1 - The installer can be downloaded through the Microsoft Update service or by downloading the Windows Installer 3.1 redistributable from the Microsoft download page.

Compatibility with Operating System Versions

Phoenix is compatible with the following desktop operating system versions with the indicated language packs with a Regional Options setting of English (United States):

Compatible Operating Systems Windows XP SP3 English (United States), Kanji (Japan), French (France)

Installation System and hardware requirements

Compatible Operating Systems Windows Vista English (United States), Kanji (Japan), French (France), Spanish (Spain), German (Germany), Simplified Chinese (China) SP2 32 bit Windows 7 SP1 32 and 64 bit English (United States), Kanji (Japan), French (France), Spanish (Spain), German (Germany), Simplified Chinese (China)

Phoenix is compatible with the following server operating systems versions (for direct access or for access via a desktop with a terminal server application), with English (United States) operating system/language pack and Regional Options setting of English (United States):

Windows Server 2003 Standard SP2 32 bit Windows Server 2008 R2 SP1 64 bit

Phoenix is compatible with the following terminal server applications:

Citrix Presentation Server (accessing a Pharsight application on a Windows Server 2003 Standard SP2 (32 bit) server) Citrix Xenapp (accessing a Pharsight application on a Windows Server 2008 R2 SP1 (64 bit) server) Microsoft Terminal Server

Compatible third-party software

Phoenix is compatible with the following third-party software.

Compatibility with Third Party Application Versions Microsoft Office 2003, 2007, and 2010 (32 bit) SAS - versions up to and including 9.3 (32 bit and 64 bit) NONMEM V, VI, and 7.12 (32 bit) S-Plus 7, 8.1.1, and 8.2 SigmaPlot 9.01, 10, 11.1, 11.2, 12, 12.1, and 12.2 (32 bit and 64 bit) R - versions up to and including 2.14.1 (32 bit and 64 bit) PsN - versions up to and including 3.4.2 (32 bit and 64 bit) Xpose 4 Package for R - version corresponding to the R version being used

Phoenix Getting Started Guide See also Phoenix 64 bit Versus 32 bit Version on page 13.

Note: When Phoenix is installed and configured to run on a Windows Operating

System where its Regional Language settings are not US English, SAS, SigmaPlot and S-PLUS objects cannot be executed. Watson LIMS dll is not supported on Vista or Windows 7. It is only supported on XP.

Compatible Pharsight software

Software PKS (Pharsight Knowledgebase Server) 4.0.1, 4.0.2, 4.0.3, and 4.0.3a

Requirements See the corresponding PKS Release Notes for a list of supported and tested software and operating systems.

Phoenix can be installed on the same computer with all current Pharsight software, including WinNonlin 5.3 with or without the IVIVC Toolkit.

Hardware requirements

Minimum Hardware requirements Item Processor RAM Hard drive space Requirement Intel Core 2 Duo 2.0 Ghz. or a CPU of EQUIVALENT processing power 2 gigabytes of RAM 300 megabytes

Installation Installing Phoenix

Installing Phoenix
The instructions for installing Phoenix WinNonlin, Phoenix Connect, and Phoenix NLME are the same. Before installation: The following steps are optional and only apply if S-PLUS is going to be used with Phoenix but has not yet been installed. 1. If S-PLUS or later is not already installed then install S-PLUS according to the instructions on the S-PLUS installation CD. 2. Add the directory path to the S-PLUS installation to the System variables Path statement. For example, if S-PLUS 7.0 is installed in the default location, then the System variable Path statement must include the line C:\Program Files\Insightful\splus70\cmd.

3. For more on editing System variables, refer to this Microsoft Knowledgebase article. Installation notes: To allow Phoenix to correctly process projects created in English locales, standards and formats must be set to US English with Customized Regional Options. These options are a decimal setting of (.) for numbers and currency and, finally, a List Separator of (,). If Phoenix is being installed on a computer that uses Windows Vista, see Windows Vista installation on page 11 for post-installation instructions. If Phoenix is being installed on a computer that does have any .NET framework or a .NET framework prior to 2.0 Service Pack 1, see Systems without .NET 2.0 SP1 or higher on page 6 for an important installation warning. Install Phoenix: There are two ways to start the Phoenix installation process, depending on which delivery method was used to acquire Phoenix. 1. Extract the ZIP file that contains the installation files. 2. Double-click Setup.exe to run the Phoenix Installation wizard. Vista and 7: For Windows Vista, Windows 7, and Windows Server: right-click Setup.exe and select Run As. Enter Administrative credentials in the User Account Control dialog.

Phoenix Getting Started Guide OR 1. Insert the Phoenix CD into the computers CD or DVD drive. 2. If the Phoenix Installation Wizard does not start automatically: Double-click the My Computer icon on the desktop or select My Computer in the Start menu. Open the Phoenix CD to display its contents. Double-click Setup.exe to run the Phoenix Installation wizard.

Vista and 7: For Windows Vista, Windows 7, and Windows Server: right-click Setup.exe and select Run As. Enter Administrative credentials in the User Account Control dialog.

Setup.exe detects the operating system and starts the appropriate executable.

Systems without .NET 2.0 SP1 or higher

A forced reboot might occur during the installation process if .NET 2.0 Service Pack 1 is not installed. The reboot occurs before the Phoenix Setup wizard is started. This primarily occurs on computers running Windows XP that do not have any .NET framework components installed. If the computer reboots, start the installation process again by double-clicking

Setup.exe after the operating system restarts.

Installation Installing Phoenix Continue the installation: 1. The Phoenix Setup wizard is started.

2. Click Next. The Sublicense Agreement screen is displayed.

3. Read the license agreement. To accept its terms and proceed with the installation, select the I AGREE option button and click Next.

Note: If there are any questions about the agreement, then contact Pharsights
sales department at [email protected].

Phoenix Getting Started Guide The User Information screen is displayed.

4. Enter the appropriate user information and click Next. 5. The Destination Folder screen is displayed. Accept the default installation directory or choose a directory in which to install Phoenix. Click Next. The Select Installation Type screen is displayed.

6. Select an installation type and click Next. Typical is the default installation type. MPICH2, the Job Management System (JMS), and the JQS (Job Queue System) are not installed when Typical is selected.

Installation Installing Phoenix To install MPICH2, use Typical first and then restart the installation program and use the Custom option to install MPICH2. If Typical is selected, the Ready to Install the Application screen is displayed. Complete This option is not recommended.

Custom allows the user to select the items to install. Use Custom to install the MPICH2 software for multiple-CPU and CPU core processing, the JMS, and the JQS.

To change the passphrase from the default, select MPI_PHRASE and click the Set button. In the Property Value field, enter a new passphrase and click OK to close the dialog.

When the Phoenix Job Processing Server (part of the JMS) is installed the default location for the Job Processing Server's workspace is C:\Phoenix.JPS. On computers where the C: drive is not available, the workspace must be changed to a valid writable location, while keeping the directory

Phoenix Getting Started Guide name. Both instances where the workspace is listed in the jps.exe.config file must be identical. Custom allows users to make additional choices about what is installed. If Custom is selected, the Select Features dialog is displayed. Click Next to continue the installation. The Ready to Install the Application screen is displayed.

7. Use the Back button to return to the previous screens to make any changes to the installation. 8. Click Next to continue the installation process. If a WinNonlin 5.3 license is already installed, the Phoenix installation process asks whether or not to use it.

9. Click Yes to use the WinNonlin license, or No to use a new license. CAUTION: Only click Yes if the WinNonlin license is current. For descriptions of the Phoenix plug-ins and features that different WinNonlin licenses activate, see WinNonlin 5.3 license holders on page 24.

10

Installation Installing Phoenix

For a description of where the WinNonlin license file is placed when users select to add it, see Adding a WinNonlin 5.3 license during installation on page 12. If they are not already installed, the LegacyWNL components and Microsoft Visual C++ 2005 Redistributable are installed. 10. Click the OK button to exit the Phoenix installation wizard. The Phoenix has been successfully installed screen is displayed.

11. Click Finish to finish the installation. Users are prompted to restart their computers. The Phoenix installation process is finished. If the Complete installation type was selected, then users need to open TCP ports on their computer to use the MPICH2 software. See Opening TCP ports for MPICH2 on page 15 for instructions on opening TCP ports.

Windows Vista installation

Phoenix requires Microsoft's .NET Framework 2.0 Service Pack 1 or higher. By default, Windows Vista does not include the .NET framework. If .NET 2.0 SP1 or higher is not already installed, then the latest version of .NET can be downloaded from the Windows Update site.

11

Phoenix Getting Started Guide

Adding a WinNonlin 5.3 license during installation

By default, the WinNonlin license file lservrc is located in C:\Program Files\Pharsight\WinNonlin. If a user chooses to add the WinNonlin license during the installation process, it is copied to the default Phoenix installation directory C:\Program Files\Pharsight\Phoenix\application\Services\Licensing in both Windows XP and Vista.

Modifying, updating, or removing a Phoenix installation

If Phoenix is already installed, then users can double-click the Setup.exe or the Setup.msi file to update or modify a Phoenix installation. Double-click the Setup.exe or the Setup.msi file. The Phoenix Application Maintenance screen is displayed.

Select a maintenance operation and click Next.

Modify is the default selection type. Modify allows users to make additional choices about what is installed. If Modify is selected, the Select Features dialog is displayed. Repair reinstalls parts of Phoenix that need to be corrected or updated If Repair is selected, the Ready to Repair the Application screen is displayed. 12

Installation Phoenix 64 bit Versus 32 bit Version

Phoenix is re-installed based on the user selections made when Phoenix was originally installed. Remove uninstalls Phoenix. If Remove is selected, the Phoenix Uninstall screen is displayed.

Note: During the uninstall process, if a dialog is displayed stating that the application
called MPICH2 Process Manager needs to be closed before continuing, accept the default to automatically close the application and click OK.

Phoenix 64 bit Versus 32 bit Version

Both the 64 bit and 32 bit versions of Phoenix, namely Phoenix and Phoenix32, are available to users with 64 bit operating systems. Users of 32 bit operating systems are unable to launch Phoenix as a 64 bit application. Any features not available in Phoenix 64 bit are available in the 32 bit version, on the same system.

Functional differences between 32 bit and 64 bit

Phoenix 64 bit has all the same features as Phoenix running in 32 bit, except for the specific differences outlined here. The following functionality descriptions refer only to the 64 bit version. Executables: Executables that do not support 64 bit fail validation if the user tries to execute them. Users can still open, save, create and interact (limited in some cases) with all executables but are not able to execute them if not supported in 64 bit. These executables are: SigmaPlot AP File I/O Not all file formats supported in 32 bit can be supported in 64 bit. Primarily due to COM interaction with legacy WNL components used to read the file formats. This is the case for importing files from the desktop as well as PKS. (The exception is WNL 5 scenarios from PKS. Scenarios are wellformed workspaces that can be loaded without additional user intervention in a separate process space which is why they are supported.) PWO, PMO, PTO, PCO, BQL, TDF, XML, LML, CMD, IVC, MAP WNL workspaces (WSP, PWS) 13

Phoenix Getting Started Guide ODBC Import In the case of the legacy files the user are given a warning that the file format is not supported in 64 bit. For ODBC, the menu options are not displayed to the user.

Compatibility Exceptions
Projects created in the 32 bit or 64 bit versions of the application work in both versions. JMS/RMS work with Phoenix regardless of the bit level of the server or client components. 32 bit Phoenix can communicate with 64 bit JMS/RMS, 64 bit Phoenix can communicate with 32 bit JMS/RMS. Phoenix works with Office 32 bit (64 bit Office is not a supported platform). PKS works with both versions of Phoenix.

Job Management Service (JMS)

The JMS queue and job processor components (queue JQS, job processor JPS) support 32 and 64 bit versions. The AnyCPU versions are the default. If a user or admin needs to use the 32 bit versions of JQS or JPS they are also installed as jqs32.exe and jps32.exe. To use the 32 bit versions the services must be stopped and the 32 bit versions must be renamed to jqs.exe and jps.exe respectively.

Configuring Phoenix for international use

When Phoenix is installed on systems that do not use the United States region, then some regional display information must be changed before Phoenix can be used. CAUTION: If the settings are not changed then Phoenix cannot correctly run projects that are created in the English (United States) region. In the Control Panel, open the Regional and Language Options dialog. In the Regional and Language Options dialog, select English (United States) as the region. If the region information cannot be changed, then users must set the decimal symbol to a period (.) for numbers and currency, and the list separator symbol to a comma (,). Click the Customize button. The Customize Regional Options dialog is displayed.

14

Installation Opening TCP ports for MPICH2 In the Decimal symbol menu, change the decimal symbol to a period (.). In the List separator menu, select a comma (,). Select the Currency tab. In the Decimal symbol menu, change the decimal symbol to a period (.). Click OK and then Apply to save the changes.

Opening TCP ports for MPICH2

MPICH2 is an implementation of the Message Passing Interface (MPI) standard, which allows users to process Phoenix models using multiple CPUs or CPUs with multiple cores.

Note: Phoenixs MPI feature can be used in a networked computing environment,

where multiple computer are used to run Phoenix models. Please contact your IT support personnel for help with opening ports in a networked computing environment. MPICH2 must use certain TCP ports. If TCP ports are not opened for MPICH2, and the computer uses a software firewall, then the firewall might display alerts each time MPICH2 is run. The multiple alerts are displayed because the executable that uses MPICH2 is compiled dynamically with each execution, so adding an exemption in a firewall for MPICH2 might work only temporarily. Users can restrict MPICH2 to use a range of ports, and open those ports in a firewall to avoid the multiple warnings. Users can also set a system environment variable named MPICH_PORT_RANGE with a value of <port range start>:<port range end>. This restricts MPICH2 to only use the given port range. Pharsight recommends using ports 10000 to 11000 for MPICH2. For example, use MPICH_PORT_RANGE=10000:11000 to restrict to the range to 10000-11000.

15

Phoenix Getting Started Guide Pharsight provides a batch file called mpiPortTool.bat that allows users to automatically open and close ports for MPICH2 in Windows Firewall. Users must be logged in as an administrator for the batch file to work correctly. The default location of the batch file is C:\Program Files\Pharsight\MPICH2\tools\mpiPortTool.bat. The batch file is installed only if MPICH2 is installed. Double-click mpiPortTool.bat. A command prompt is opened that asks users what port range to use.

At the prompt, enter a beginning port number, such as 10000. Press ENTER. Enter an ending port number such as 11000. Press ENTER.

The batch file then presents three options that allow users to open ports, close ports, or quit.

16

Installation Opening TCP ports for MPICH2

Press 1 to add the port numbers to Windows Firewall. A second command prompt is opened and adds the selected port range. The batch file also creates a system environment variable that includes the port numbers.

17

Phoenix Getting Started Guide

18

Chapter 2

Licensing
Installation and renewal of Phoenix software licenses

The chapter contains the following topics: Phoenix Licensing Service on page 19 License key code types on page 19 Product and authorization codes on page 20 Plug-in licenses on page 21 WinNonlin 5.3 license holders on page 24 License Management on page 24 License Server Management on page 26

Phoenix Licensing Service

The Phoenix Licensing Service is the system Phoenix uses to manage user licenses. When a user starts Phoenix for the first time the Licensing Service is the first Phoenix service that is initialized, and the No Framework License message is displayed if no license is detected. The Licensing Service is integrated into the Phoenix Preferences menu, which can be accessed by selecting Preferences in the Edit menu. Users have several options to install or acquire a license. Users can activate their copy of Phoenix by using online and offline activation, or users can connect to a license server to acquire a license for online or offline use.

License key code types

Phoenix requires the installation of a license key code. There are three types of license key codes:

19

Phoenix Getting Started Guide 1. Node - a license key code that activates the software on the machine on which it is installed. The license agreement restricts installation of the software and license to a single personal computer (PC) per node license. 2. Floating - a license key code that enables multiple PCs in a networked environment to run Phoenix using a shared pool of software licenses. The number of simultaneous users is limited to the total number of licenses on the license server. 3. Commuter - a floating license key code that is retrieved from a network. Commuter licenses give users temporary offline authorization to use Phoenix while away from the network where their floating license server resides. Commuter licenses can be used for a specified period of time and are subject to a hold time during which they cannot be checked out by another user. This protects users who need to make changes to a Phoenix project after they close Phoenix from immediately losing their license key to another user on the network. Customers must work with Pharsight Sales and the Licensing Administrator to determine how many of their floating licenses should contain the commuter feature and the length of time that commuter enabled licenses are valid after they have been checked out from the license server. The timeout period can not be altered after the license has been installed.

Note: The commuter license option is only available if the Sentinel RMS 8.x
license server is used with Phoenix.

Product and authorization codes

A product code and an authorization code are included with each license or set of licenses purchased. The primary delivery system for acquiring the Phoenix application is downloading the installation files from a Pharsight server. Pharsights download and support page is located at http://www.pharsight.com/support/ support_home.php. When Phoenix is purchased, customers are sent an email with the four things necessary to use Phoenix: The application and license server download link. The authorization code. The product code. The license code generation Web site link.

20

Licensing Phoenix Licensing Service

A CD can be ordered for users who want a physical medium. To purchase a CD, contact Pharsight's sales department at: [email protected] 1-888-708-7444 (US only) +1-919-852-4685 Fax: +1-973-828-0273 For mail shipments, the product and authorization codes are located on the packing slip shipped with the software, and on the products CD jewel case. E-mail: Telephone: Please include the product code in all correspondence with Pharsight Corporation about the product and its license, including license renewals, software updates, and product upgrades.

Plug-in licenses
Phoenix uses a plug-in architecture to create system functions. Phoenix allows users to enable, disable, configure, and create plug-ins. All Phoenix framework functions and plug-ins require a license before they can be used. The following table shows which framework features and plug-ins are enabled by the different license types. Some features and plug-ins require customers to purchase one or more licenses before they can be used. The features and plug-ins that are enabled by each license are listed in the following table.

Phoenix plug-in license matrix Feature/Plug-in Data objects Append Worksheets BQL Column Properties Column Transformation Crossproduct Worksheets Filter Worksheet Join Worksheets Merge Worksheets Pivot Worksheet Rank Worksheet Split Worksheet X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Phoenix Connect Phoenix WinNonlin Phoenix NLME IVIVC Toolkit 2.0

21

Phoenix Getting Started Guide

Phoenix plug-in license matrix Feature/Plug-in Stacker Plotting objects Bar Plot Column Plot Box Plot Histogram XY Plot QQ Plot Scatter Plot Matrix NCA and Toolbox objects NCA Bioequivalence Crossover Deconvolution Descriptive Stats Linear Mixed Effects NonParametric SemiCompartmental WNL5 Classic Modeling objects Dissolution Model Indirect Response Model Linear Model Michaelis-Menten Model PD Model PK Model PK/PD Model WNL5 ASCII Format model WNL-Phoenix Modeling object Phoenix Model (individual) Phoenix Model (population) Phoenix Model Comparer X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Phoenix Connect X Phoenix WinNonlin X Phoenix NLME X IVIVC Toolkit 2.0

22

Licensing Phoenix Licensing Service

Phoenix plug-in license matrix Feature/Plug-in IVIVC objects IVIVC Levy Plot Loo-Riegelman Wagner-Nelson Reporting object Table NONMEM object NONMEM Shell NONMEM Comparer SAS object SAS Shell SigmaPlot object SigmaPlot Shell S-PLUS object S-PLUS Dataframe Import S-PLUS Script S-PLUS Worksheet Export R Script object R script X X X X X X X X X X X X X X X X X Phoenix Connect Phoenix WinNonlin Phoenix NLME

IVIVC Toolkit 2.0

PKS Connectivity CDISC import and export ODBC Connectivity Word Export Edit in Excel Plug-in APIs Phoenix Framework

X X X X X X X X X X X X X X X

23

Phoenix Getting Started Guide

WinNonlin 5.3 license holders

Users who have WinNonlin 5.3 licenses can use Phoenix with no intervention from Pharsight as long as the WinNonlin license is current. During the installation process Phoenix looks for an existing WinNonlin license. If it finds one, it gives the user the option of using it. If a user chooses to use the existing license, a copy of the license file, lservrc, is written to the default Phoenix license file location at C:\Program Files\Pharsight\Phoenix\application\Services\Licensing. Users can also copy and paste the lservrc file from the WinNonlin installation directory (C:\Program Files\Pharsight\WinNonlin by default) to the Phoenix licensing service directory (C:\Program Files\Pharsight\Phoenix\application\Services\Licensing by default). A WinNonlin 5.3 Professional license is equivalent to the Phoenix WinNonlin license. A WinNonlin 5.3 Enterprise license is equivalent to the combination of the Phoenix WinNonlin and Phoenix Connect licenses.

WinNonlin 5.3 floating license servers

WinNonlin license servers are not detected during the installation process on Windows Vista. The license server IP address must be entered manually in the License Server Management screen in the Preferences dialog.

License Management
The License Management screen allows users to see which license types are available and acquired, as well as the different plug-ins they allow users to access.

24

Licensing License Management

The License Management dialog has five fields:

License Management fields Field Name Type Commuter Status Expires Function Lists the names of available licenses. Lists whether the license is local (node) or network (floating or commuter). Lists floating licenses that are available to be commuted. Lists the status (Available, Acquired, etc.) of licenses Lists the license expiration date.

Use the License Management dialog: 1. Select Edit > Preferences. The Preferences dialog is displayed. Expand items in the Preferences menu tree by clicking the (+) signs.

2. Select Licensing > License Management in the Preferences dialog menu tree.

25

Phoenix Getting Started Guide

Node licenses
There are no options for node licenses in the License Management screen.

Floating licenses
1. To use a floating license, click a network license name in the Name column. The license status is changed to Acquired. 2. Click the license name again to return the license. The license status is now Available.

Commuter licenses
1. If a commuter license is available, click the Request button in the Commuter column. 2. If the commuter license is acquired, and its status is changed to Commuting. 3. The date the commuter license expires is listed in the Expires column. 4. To return a commuter license, click the Release button to release the license. 5. Click the Refresh button to update the list of available licenses.

License Server Management

The License Server Management screen allows users to add license server IP addresses to Phoenix. The number of available license servers is determined by the customer. Some versions of Sentinel license servers support redundant license servers. The License Server Management screen has three fields: Name, IP Address, and Status. The Name field contains the name of the license server, the IP Address field contains the IP address of the license server, and the Status field contains the connection status.

26

Licensing License Server Management

Use the License Server Management screen: 1. To add a license server, enter the IP address of the server in the IP Address or Host Name field beside the Add button and click the Add button. 2. To remove a floating license server, enter the IP address of the server in the IP Address field and click the Remove button. Click the Refresh button to update the list of available license servers.

27

Phoenix Getting Started Guide

28

Chapter 3

Testing the Installation

Confirming proper installation of the main Phoenix functions

The following instructions test the installation of Phoenix by using a number of the sample files provided with the software. This chapter is not intended as a full validation of the product. It is intended to test for proper installation of major components of the application. A complete validation kit is available from Pharsight Corporation. Contact the Pharsight sales department for more information. Users interested in a validation kit should send an e-mail to [email protected], or phone sales at 1-888-7087444 (US only) or +1-919-852-4685 (international).

Start Phoenix and create a new project

1. In the Windows Start menu, select All Programs > Pharsight > Phoenix > Phoenix to start Phoenix.

Note: AutoPilot users should run All Programs\Pharsight\Phoenix\Phoenix32 as opposed to All Programs\Pharsight\Phoenix\Phoenix when running on 64 bit operating systems. The Phoenix
desktop icon should be updated to reference Phoenix32 executable as well. 2. Select File > New Project to create a new project. A new project is created in the Object Browser. 3. Name the new project Install Test. The left panels default view is the Object Browser, which contains the project, and the other folders and objects that are contained in the project. The right viewing panels default view is blank, unless one of the project folders or the workflow is selected.

29

Phoenix Getting Started Guide

Confirm license installation

The ability to execute different Phoenix plug-ins depends on the license type installed. Use the Preferences dialog to check the installed Phoenix license(s). 1. Select Edit > Preferences to access the Preferences dialog. 2. In the Preferences menu tree, select Licensing > License Management to access the list of available licenses. 3. Confirm that the purchased license or licenses are listed in the Licenses panel. 4. Click OK to exit the Preferences dialog. 30

Testing the Installation Start Phoenix and create a new project

Confirm plug-in startup

The Phoenix architecture is based on a series of plug-ins that allow different features to be enabled or disabled. Phoenix initializes these plug-ins when the application starts. The default setting is for all plug-ins to initialize when Phoenix starts. The plug-in initialization is independent of the installed license(s). 1. Select Edit > Preferences. The Preferences dialog is displayed. Expand items in the Preferences menu tree by clicking the (+) signs.

2. In the Preferences menu tree, click the (+) sign beside Plugins to view the list of available plug-ins. The Plugins menu contains three tabs: General, System, and Nonloaded. Each plug-in has two possible states, Started and Stopped. All plug-ins are started the first time Phoenix is started. 3. Select the General, System, and Non-loaded tabs to see the review the state of each plug-in type and to confirm they are started. 4. Click OK to exit the Preferences dialog.

Import a data set

The data set Bguide1.dat is used to test key Phoenix functions. 1. Select File > Import or click the Import is displayed. button. The Open File(s) dialog

2. Navigate to the Phoenix examples subdirectory, which by default is located at

C:\Program Files (x86)\Pharsight\Phoenix\application\Examples (for 64 bit, go to C:\Program Files (x86)\Pharsight\Phoenix\application\Examples).

3. Select the file Bguide1.dat and click Open. The Worksheet Import Options dialog is displayed. The dialog is used to assign options for how the data are imported and presented. 4. Click Finish. The data set is added to the projects Data folder. 5. View the data set by selecting it in the Data folder. The worksheet is displayed in the Grid tab, which is located in the right viewing panel.

Create a plot
1. Select the workflow object Insert > Plotting > XY Plot. in the Object Browser and then select

31

Phoenix Getting Started Guide The XY Plot object can also be added by right-clicking the workflow object and selecting New > Plotting > XY Plot. Any object can be added by selecting New in the workflow menu.

The XY Plot object is added to the workflow in the Object Browser. Objects automatically open in the right viewing panel when they are inserted in a workflow. Each objects default view is the Setup tab, which contains all the steps necessary to set up an object. 2. Map the data set Bguide1 as the input source for the XY Plot object: Use the pointer to drag the Bguide1 worksheet from the Data folder to the XY Data Mappings panel. or In the XY Plots XY Data Mappings panel click the Select source ton to open the Select Object dialog. Select Bguide1 under Data. Click OK. The Bguide1 data set is mapped to the XY Plot object. 3. Use the option buttons in the XY Data Mappings panel to map the data types to the following contexts: Map Subject to the Group context. Map Time to the X context. Map Conc to the Y context. button. The results are displayed on the Results tab. but-

4. Click the Execute XY Plot results

32

Testing the Installation Start Phoenix and create a new project

Now use the Bguide1 data set to test the Table object and its summary statistics function.

Create a table
1. Add the Table object to the workflow. Select the workflow object in the Object Browser and then select Insert > Table > Table. or Select the workflow in the Object Browser. The workflow Diagram tab is displayed in the right viewing panel. Click the Table button in the Object toolbox. The Table object is added to the Diagram tab.

The Table object is added to the workflow in the Object Browser. 2. Map the data set Bguide1 as the input source for the Table object: Select the Table object in the Object Browser to view the objects Setup tab. Use the pointer to drag the Bguide1 worksheet from the Data folder to the Table objects Main Mappings panel. or In the Tables Main Mappings panel click the Select source open the Select Object dialog. Select Bguide1 under Data. Click Select. button to

The Bguide1 data set is mapped to the Table object.

33

Phoenix Getting Started Guide Use the Options tab to specify which table type the Table object uses. The Options tab is located underneath the Setup tab. Table Options tab

3. In the Table Type menu, select Table 1 - Column Summary by Row Stratification. 4. Select the Page Break on Row Stratification check box. 5. Use the option buttons in the Main Mappings panel to map the data types to the following contexts: Map Subject to the Stratification Row context. Leave Time mapped to None. Map Conc to the Data context.

6. Select the Statistics tab, which is located underneath the Setup tab. 7. Click the Select All button to select all output statistics. 8. Click the Execute button. The results are displayed on the Results tab.

34

Testing the Installation Start Phoenix and create a new project The results are presented as three HTML tables. Compare the tables in the Results tab to the tables pictured below. Tables 1 and 2

35

Phoenix Getting Started Guide Table 3

36

Testing the Installation Confirm model functions

Confirm model functions

This section tests examples of noncompartmental analysis, pharmacokinetic modeling, bioequivalence, and population modeling.

Noncompartmental analysis
1. Select File > Import or click the Import is displayed. button. The Open File(s) dialog

2. Navigate to the Phoenix examples subdirectory, which by default is located at

C:\Program Files(x86)\Pharsight\Phoenix\application\Examples (for 64 bit, go to C:\Program Files (x86)\Pharsight\Phoenix\application\Examples).

3. Select the Legacy WinNonlin subdirectory. 4. Select Profiles.pmo and click Open. The Data Import Wizard is displayed. The wizard is used to assign options for how the data are imported and presented. 5. Click Finish. The data set is added to the projects Data folder. A file in PMO (Pharsight Model Object) format is added to the Data folder as one or more workbook objects. A .pmo file also adds one or more operational objects to the project. The Profiles.pmo file adds: A data set in workbook form (profiles). Data sets in workbook form for partial areas and dosing (Profiles_sources). An NCA model object (model 200) named Profiles. 6. Click the (+) symbols beside profiles and Profiles_sources in the Data folder to view the data sets worksheets. 7. Select the NCA model object Profiles in the Object Browser. The NCA objects Setup tab is displayed in the right viewing panel. CAUTION: Models saved in PMO format contain all the necessary data mappings and option settings. Do not change these settings. 8. Select items in the NCA model objects Setup tab list to explore the models data mappings and option settings. 9. Click the Execute button. The Results are displayed on the Results tab.

37

Phoenix Getting Started Guide

Text Output
The Core output contains the model settings and the same data as the worksheets, but presented in plain ASCII text. If there were errors in the model they would be listed here. Core output text file
Subject=1,Form=Capsule Date: 4/29/2009 Time: 13:39:21

WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 1.0 Core Version 04Jun2007 Settings -------Model: Plasma Data, Extravascular Administration Number of nonmissing observations: 12 Dose time: 0.00 Dose amount: 100.00 Calculation method: Linear Trapezoidal with Linear Interpolation Weighting for lambda_z calculations: Uniform weighting Lambda_z method: Find best fit for lambda_z, Log regression

Summary Table ------------Time Conc. Pred. Residual AUC AUMC Weight min ng/ml ng/ml ng/ml min*ng/ml min*min*ng/ml ------------------------------------------------------------------------------0.0000 0.0000 0.0000 0.0000 5.000 340.3 850.8 4254. 10.00 1914. 6487. 5.636e+004 15.00 2069. 1.644e+004 1.818e+005 20.00 1471. 2.529e+004 3.329e+005 30.00 788.8 3.659e+004 5.983e+005 45.00 * 496.4 460.9 35.54 4.623e+004 9.434e+005 1.000 60.00 * 372.8 357.2 15.63 5.275e+004 1.279e+006 1.000 90.00 * 204.3 214.6 -10.33 6.141e+004 1.890e+006 1.000 120.0 * 124.1 128.9 -4.852 6.633e+004 2.389e+006 1.000 180.0 * 39.25 46.52 -7.266 7.123e+004 3.048e+006 1.000 240.0 * 19.32 16.79 2.531 7.299e+004 3.399e+006 1.000

38

Testing the Installation Confirm model functions

The Settings file lists all the settings used to specify the noncompartmental analysis. Settings text file
/********************************* Begin Mappings *********************************/ Main : install Test.Data.profiles.Sheet1 Sort : Subject, Form Carry : Time : Time Concentration : Conc Dosing : install Test.Data.Profiles_sources.Dosing Sort : Subject, Form Dose : Dose Time of Dose : Time Tau : Tau Slopes : (Internal) Partial Areas : install Test.Data.Profiles_sources.PartialAreas Sort : Subject, Form Area # : Curve Label : Start Time : Lower End Time : Upper Therapeutic Response : (Internal) Units : (Internal) Parameter Names : <None> /********************************* End Mappings *********************************/

Plasma Model Linear Trapezoidal Linear Interpolation Sparse = False Dose Type = Extravascular Dose Normalization = None Exclude Insufficient Profiles = False

39

Phoenix Getting Started Guide

Output Data
The NCA object creates seven results worksheets: Dosing Used, Exclusions, Final Parameters, Final Parameters Pivoted, Plot Titles, Summary Table, and Partial Area Labels. Selections from the Final Parameters and Summary Table worksheets are shown below. Final Parameters worksheet

40

Testing the Installation Confirm model functions Summary Table worksheet

41

Phoenix Getting Started Guide

Plots
A total of 12 plots are generated; one for each of two formulations, for each of the six subjects. The first two charts for subject one are shown below. Observed Y and Predicted Y vs X for Subject 1

Observed Y and Predicted Y vs X for Subject 1

42

Testing the Installation Confirm model functions

Pharmacokinetic modeling
1. Select File > Import or click the Import is displayed. button. The Open File(s) dialog

2. Navigate to the Phoenix examples subdirectory, which by default is located at

C:\Program Files(x86)\Pharsight\Phoenix\application\Examples (for 64 bit, go to C:\Program Files (x86)\Pharsight\Phoenix\application\Examples).

3. Select the Legacy WinNonlin subdirectory. 4. Select Exp1.pmo and click Open. The Data Import Wizard is displayed. The wizard is used to assign options for how the data are imported and presented. 5. Click Finish. The data set is added to the projects Data folder. The Exp1.pmo file adds: A data set in workbook form (exp1). Data sets in workbook form for dosing and the stripping dose (Exp1_sources). A PK Model object named Exp1. 6. Click the (+) symbols beside exp1 and Exp1_sources in the Data folder to view the data sets worksheets. 7. Select the PK Model object Exp1 in the Object Browser. The PK Model objects Setup tab is displayed in the right viewing panel. 8. Select items in the PK Model objects Setup tab list to explore the models data mappings and option settings. The imported PK Model object uses PK Model 13, which is a two compartment model with 1st order absorption. 9. Click the Execute button. The Results are displayed on the Results tab.

43

Phoenix Getting Started Guide

Worksheet results
The PK Model objects output worksheets partially include Condition Numbers, Diagnostics, Dosing Used, Final Parameters, Initial Estimates, Secondary Parameters, and Summary Table. The Final Parameters, Secondary Parameters, and Summary Table worksheets are shown below. Final Parameters worksheet

Secondary Parameters worksheet

44

Testing the Installation Confirm model functions Summary table worksheet

45

Phoenix Getting Started Guide

Text Output
The Core output text results include all model settings and iterations, including the output from the worksheets. Any model errors would be listed here. Core output text file
WinNonlin 6.0.0.1645, WnlPKCore Library: 1.0.5.0 Date: 04/29/2009 Time: 14:35:48 WINNONLIN NONLINEAR ESTIMATION PROGRAM Core Version 18June2007

Listing of input commands TITL 1 Example one - Fitting model 13 in the compiled library : single dose TITL 2 Using Weight Command and Curve Stripping to get Initial Estimates MODEL 13 NVAR 2 NPOI 1000 XNUM 1 YNUM 2 NCON 4 CONS 2,1,2,0 METH 2'Gauss-Newton (Levenberg and Hartley) ITER 50 WEIG -1 MISS 'Missing' DATA 'WINNLIN.DAT' BEGI

Computation of initial estimates completed.

46

Testing the Installation Confirm model functions

The Settings file lists all the settings used to specify the noncompartmental analysis. Settings text file
/********************************* Begin Mappings *********************************/ Main : install Test.Data.exp1.Sheet1 Sort : Time : Time Concentration : Conc Carry : Dosing : install Test.Data.Exp1_sources.Dosing Sort : Time : Time Dose : Dose Initial Estimates : (Internal) Units : (Internal) Stripping Dose : install Test.Data.Exp1_sources.Stripping Sort : Dose : Dose

***** Other Parameters *****

/********************************* End Mappings *********************************/

PK 13 - [Exp1] Gauss-Newton (Levenberg and Hartley) Convergence criteria of 0.0001 used during minimization process 50 maximum iterations allowed during minimization process Weighted analysis using WEIGHT = -1

Plots
The plot results include Observed Y and Predicted Y vs X, Partial Derivatives Plot, Predicted Y vs Observed Y, Residual Y vs Predicted Y, Residual Y vs X, Weighted Predicted Y vs Observed Y, Weighted Residual Y vs Weighted Predicted Y, and Weighted Residual Y vs X.

47

Phoenix Getting Started Guide Some plot results are shown below. Observed Y and Predicted Y vs X

Predicted Y vs Observed Y

48

Testing the Installation Confirm model functions Residual Y vs X

Weighted Residual Y vs Weighted Predicted Y

Bioequivalence
Import the data: 1. Select File > Import or click the Import is displayed. button. The Open File(s) dialog

2. Navigate to the Phoenix examples subdirectory, which by default is located at

C:\Program Files(x86)\Pharsight\Phoenix\applica-

49

Phoenix Getting Started Guide

tion\Examples (for 64 bit, go to C:\Program Files (x86)\Pharsight\Phoenix\application\Examples).

3. Select the file Seq2Per4.csv and click Open. The Worksheet Import Options dialog is displayed. The dialog is used to assign options for how the data are imported and presented. 4. Click Finish. The data set is added to the projects Data folder. Set up the average bioequivalence model: 1. Select the workflow in the Object Browser and then select Insert > NCA and Toolbox > Bioequivalence. The Bioequivalence object is added to the workflow in the Object Browser.

Note: The default settings for a new Bioequivalence model are Crossover as the
type of study and Average as the type of bioequivalence. 2. Map the data set Seq2Per4 as the input source for the Bioequivalence object: Use the pointer to drag the Seq2Per4 worksheet from the Data folder to the Main Mappings panel. or In the Bioequivalence Main Mappings panel click the Select source button to open the Select Object dialog. Select the Seq2Per4 worksheet under Data. Click OK.

The Seq2Per4 data set is mapped to the Bioequivalence object. 3. Use the option button in the Main Mappings panel to map AUC to the Dependent context. The following data types are automatically mapped to contexts when the data set is mapped to the Bioequivalence model. Sequence is mapped to the Sequence context. Subject is mapped to the Subject context. Period is mapped to the Period context. Formulation is mapped to the Formulation context. Use the Model tab to specify settings for Bioequivalence model options. The Model tab is located underneath the Setup tab.

50

Testing the Installation Confirm model functions

4. Ensure that Crossover is selected as the Type of study, Average is selected as the Type of Bioequivalence, and R is selected as the Reference Formulation. 5. Select the Fixed Effects tab, which is located underneath the Setup tab. Ln(x) is automatically selected in the Dependent Variables Transformation menu. Do not change this setting. button. The results are displayed on the Results tab.

6. Click the Execute

Output Data
The bioequivalence models worksheet output partially includes Average Bioequivalence, Diagnostics, Final Fixed Parameters, Final and Initial Variance

51

Phoenix Getting Started Guide Parameters, Least Squares Means, and Sequential Tests. The Diagnostics, Final Variance Parameters, and Sequential Tests worksheets are shown below. Diagnostics

Final Variance Parameters

Sequential Tests

Import the data: 1. Select File > Import or click the Import is displayed. button. The Open File(s) dialog

2. Navigate to the Phoenix examples subdirectory, which by default is located at

C:\Program Files(x86)\Pharsight\Phoenix\application\Examples (for 64 bit, go to C:\Program Files (x86)\Pharsight\Phoenix\application\Examples).

3. Select the file RTR_TRT.csv and click Open.

52

Testing the Installation Confirm model functions The Worksheet Import Options dialog is displayed. The dialog is used to assign options for how the data are imported and presented. 4. Click Finish. The data set is added to the projects Data folder. Set up the population/individual bioequivalence model: 1. Select the workflow object in the Object Browser and then select Insert > NCA and Toolbox > Bioequivalence. The Bioequivalence object is added to the workflow in the Object Browser.

Note: When multiple objects of the same type are added to a workflow they are
numbered sequentially. For example, the second Bioequivalence Model object added to this workflow is called Bioequivalence 1. 2. Map the data set RTR_TRT as the input source for the Bioequivalence 1 object: Use the pointer to drag the RTR_TRT worksheet from the Data folder to the Main Mappings panel. or In the Bioequivalence 1s Main Mappings panel click the Select source button to open the Select Object dialog. Select the RTR_TRT worksheet under Data. Click OK.

The RTR_TRT data set is mapped to the Bioequivalence 1 object. 3. Use the option buttons in the Main Mappings panel to map the data types to the following contexts: Map Sequence to the Sequence context. Map Subject to the Subject context. Map Period to the Period context. Map Trt to the Formulation context. Map AUC to the Dependent context.

Use the Model tab to specify settings for Bioequivalence model options. The Model tab is located underneath the Setup tab. 4. In the Model tab, select the Population/Individual option button.

53

Phoenix Getting Started Guide

Note: Crossover is the only study type allowed for the Population/Individual Bioequivalence model. R is automatically selected in the Reference Value menu. Do not change this setting. button. The results are displayed on the Results tab.

5. Click the Execute

The output includes analysis settings and results, and three worksheets. The first two worksheets are shown below. Population/Individual worksheet

Ratios Test=T

This concludes the installation tests.

54

Chapter 4

Installation test for Pharsight Phoenix NLME

Population modeling with an NLME license

This chapter tests Phoenixs population modeling functions. This test is not intended as a full validation of population modeling. Users who have purchased an NLME license can use the Phoenix Model object to create and test population models. After Phoenix is installed, follow the steps below to confirm that population modeling is working correctly. If any problems are encountered during this installation test, go to www.pharsight.com/support/support_home.php to report the issue.

Start Phoenix and create a project

1. In the Windows Start menu, select All Programs > Pharsight > Phoenix > Phoenix to start Phoenix. 2. Select File > New Project to create a new project. A new project is created in the Object Browser. 3. Name the new project Installation Project. 4. To verify active licenses select About Phoenix in the Help menu. For this installation test to work users must have an active license for Phoenix NLME 1.1. The left panels default view is the Object Browser, which contains the project, and the other folders and objects that are contained in the project. The right viewing panels default view is blank, unless one of the project folders or the workflow is selected.

Population modeling
This example verifies that the NLME license and the Minimal GNU C++ compiler are correctly installed and configured. If Phoenix is being used without population modeling functionality, then skip this part of the installation test. 55

Phoenix Getting Started Guide 1. Select File > Import or click the Import is displayed. button. The Open File(s) dialog

2. Navigate to the Phoenix examples subdirectory, which by default is located at

C:\Program Files\Pharsight\Phoenix\application\Examples.
3. Select theopp.csv and click Open. The Worksheet Import Options dialog is displayed. The dialog is used to assign options for how the data are imported and presented. 4. Click Finish. The data set is added to the projects Data folder. 5. View the data set by selecting it in the Data folder. The worksheet is displayed in the Grid tab. 6. Select File > Import or click the Import button.

7. Select Diagonal Model.wnlt and click Open. WinNonlin template files store information about an objects settings and internal worksheets, but do not store external data sources. The template file adds a Phoenix model. The model is a one compartment, 1st order absorption model that uses weight as a covariate. The model uses the FOCE L-B (First Order Conditional Estimation with the LindstromBates iterative algorithm) run method. Select the models Structural, Parameters, and Run Options tabs to examine the models configuration. The Parameters tab contains several sub-tabs that list fixed effects, random effects, and covariates.

8. Map the data set theopp as the input source for the Diagonal model: Use the pointer to drag the theopp worksheet from the Data folder to the Main Mappings panel. or Use the Select Object dialog to map the data set theopp to the Main Mappings panel. The theopp data set is mapped to the Diagonal model. The study variables xid, dose, time, yobs, and wt are automatically mapped to the contexts ID, Aa, Time, CObs, and wt. button. The results are displayed on the Results tab.

9. Click the Execute

56

Installation test for Pharsight Phoenix NLME Start Phoenix and create a project Verify the results: 1. Select the Verification tab.

The Verification Results state that the model successfully executed, and that no errors occurred. Verification tab

2. Select the Results tab. The Phoenix model produces four groups of output and three types: text files, plots, and worksheets. The output types are listed below.

Additional output
This section includes a text file named dmp.txt.

Output Data
The model creates twenty-two worksheet results. The Phoenix Model objects output worksheets partially include Eta, EtaCovariate, Omega, and Theta. Not all worksheets listed under Output Data contain results. Confirm the accuracy of some of the output in order to complete the installation test. In the Output Data, select the Theta worksheet and confirm that the following estimates are the same: tvKa 1.55696 tvV 0.455554 tvCl 0.0402882 stdev0 0.692202

57

Phoenix Getting Started Guide Theta worksheet

Eta worksheet

58

Installation test for Pharsight Phoenix NLME Start Phoenix and create a project

Plots
Thirty-seven plots are listed in the Plots section. Not all listed plots have results. In the Plot output, select WRES vs PRED and compare it to the screen shot below: Pop WRES vs PRED

59

Phoenix Getting Started Guide

Text Output
The Phoenix Model creates five text files. The model produces a Settings text file that lists model settings. /********************************* Begin Mappings *********************************/ Main : Installation Project.Data.theopp Sort : ID : xid Aa : dose Time : time CObs : yobs wt : wt Dosing : <None> Parameters : <None> Parameters.Mapping : (Internal) /********************************* End Mappings *********************************/

test(){ deriv(Aa = - Ka * Aa) deriv(A1 = Ka * Aa - Cl * C) dosepoint(Aa) C = A1 / V error(CEps = 1) observe(CObs = C + CEps) stparm(Ka = tvKa * exp(nKa)) stparm(V = tvV * exp(nV)) stparm(Cl = tvCl * exp(nCl)) covariate(wt) fixef(tvKa = c(, 1.54697, )) fixef(tvV = c(, 0.455465, )) fixef(tvCl = c(, 0.0402979, )) 60

Installation test for Pharsight Phoenix NLME Start Phoenix and create a project

ranef(diag(nV, nKa, nCl) = c(0.01809, 0.41265, 0.06997)) } -----------------------------------id("xid") time("time") dose(Aa<-"dose") covr(wt<-"wt") obs(CObs<-"yobs") ----------------------------------------------------------------------Run Options Method: FOCE L-B N Iter:1000 Input sorted by subject+time ODE solver method: matrix exponent Method of computing standard errors: Central Diff Hessian standard errors Confidence Level %95 Simple run was performed This concludes the installation test for Phoenix NLME. Close project without saving it.

61

Phoenix Getting Started Guide

62

Index

C
Customer support, 1 licensing, 1

W
WinNonlin installing, 5

I
Installing WinNonlin, 5

L
Licensing customer support, 1

P
Pharsight contact information, 1

T
Technical support, 1 licensing, 1

V
verify population modeling, 55
63

Phoenix Getting Started Guide

64