WinNonlin Features

http://www.pharsight.com/products/prod_winnonlin_feature.php

WinNonlin® Features

Key features of WinNonlin® Professional and Enterprise editions include the following:

• Quick data export to NONMEM®, SAS, S-PLUS®, SigmaPlot® and Excel

• Extensive built-in library of predefined models

• Support for user-defined models

• Easy data management via Excel compatible workbooks, including formulas, functions, data

import/export, missing value codes, sort, transformations and worksheet merge

• One-click export of results, plots, and tables to Microsoft Word®

• Dynamic memory management for large data sets and complex models

• Descriptive statistics, including weighted descriptive statistics

• Units definition and conversions, including the ability to specify preferred output units, units

for a dosing regimen, and unit conversions

• Noncompartmental analysis of both blood and urine data using methods for rich or sparse

datasets

• Three methods of AUC calculation: linear trapezoidal, linear/log trapezoidal, and linear

up/log down

• Support for Excel, SAS Transport, and NONMEM file formats

• Toolbox functions for deconvolution, semicompartmental modeling, nonparametric

superposition and crossover design

• Automatic determination of initial estimates for most library models

• Analysis using general linear modeling approaches, including bioequivalence tests as

appropriate

• Built-in scripting language

• Analysis can be automated or controlled from any VBA-capable tool, such as VB, Word, or

Excel

WinNonlin Enterprise edition offers additional data connectivity:

• Full integration with the PKS™ Suite of data management, automation and reporting

software

• SQL Query Builder guiding step-by-step creation of SQL queries • Custom Query Builder wizard for access to LIMS and other data sources

• A software development kit (SDK) for your IT/IS staff to use in building and installing

additional Custom Query Builder wizards for data management systems not supported by Pharsight®

Supported data sources for the WinNonlin Enterprise include:

• Any row-oriented data source that has a Microsoft’s® Open Database Connectivity (ODBC)

driver accessed via the latest version of ODBC API

• Remote Oracle databases via an Oracle-supplied ODBC driver and Oracle data connectivity

software

• SAS via a SAS-supplied ODBC driver for both remote and local access

• Commercial clinical and laboratory data management systems, including LIMS products,

such as the Watson LIMS system, via Custom Query Builder wizards supplied by Pharsight.

Details of specific WinNonlin features follow.

Noncompartmental Analysis

WinNonlin’s Noncompartmental Analysis (NCA) module computes derived PK parameters (AUC, AUCINF, Cmax, Cumulative excretion, etc.) from blood or urine data. Parameters can be calculated for single-dose or steady-state conditions, for rich or sparsely-sampled data. You can use your mouse to select the terminal elimination phase while viewing a semi-log plot, or let WinNonlin select it for you. Exclusions of individual data points for the estimation of the Lambda Z

calculation can also be specified. Area under the curve is calculated using linear, linear/log trapezoidal or linear up/log down rules. WinNonlin also computes partial AUC's even when the endpoints of the desired range are not included in the dataset.

Compartmental Modeling

WinNonlin is a powerful program for the solution of nonlinear regression problems, constrained estimation problems, systems of differential equations, and mixtures of differential equations and functions. Using WinNonlin's simulation capabilities, you can see the effect of different dosing regimens and changes in the pharmacokinetic parameters. WinNonlin's library of models includes PK, PD, PK/PD link models, indirect response models, Michaelis-Menten, and simultaneous PK/PD link models. In addition to selecting library models, WinNonlin allows you to write your own models. WinNonlin supports both ASCII and compiled user models.

Descriptive Statistics

WinNonlin's Descriptive Statistics allows users to generate summary statistics of variables in input or output grids. In addition to standard descriptive statistics, geometric mean, harmonic mean, mean and standard deviation of the logs, percentiles, and confidence intervals are included. WinNonlin also supplies weighted summary statistics. These weighted statistics include mean, standard deviation, standard error, coefficient of variation, confidence interval, and variance.

Analysis of Variance/General Linear Models

ANOVA/GLM features provide the capability to statistically analyze data from crossover and parallel studies, including unbalanced designs. You can analyze ANOVA, regression and covariance

models and calculate both sequential (Type I) and weighted squares of means (Type III). Contrasts, least squares means, parameter estimates and F-tests using user-specified error terms are available. Included is the ability to calculate bioavailability statistics: Anderson-Hauck statistic, Westlake confidence interval, classical confidence interval, power computation, two one-sided t-tests, and ratios of least squares means.

Toolbox

WinNonlin provides a suite of analysis tools called the toolbox: Nonparametric superposition helps to predict drug concentrations after multiple dosing at steady-state. Semi-compartmental modeling is used to estimate effect-site concentrations, given time and plasma concentrations. Crossover design performs nonparametric analysis of 2x2 crossover data. It calculates confidence intervals for each treatment, as well as estimating the relevance of direct, residual, and period effects. Deconvolution is used to evaluate drug release and delivery when data from a known reference input are available that enable specification the unit impulse response (UIR) function.

Graphics

WinNonlin produces presentation quality graphics quickly and easily, with flexible editing and formatting. The charts can be printed to any Windows-supported device, copied into another Windows® application or exported directly to Microsoft Word.

Template-Driven Table Generation

The Tables Wizard makes it easy to create report-ready tabular output. Using templates provided with the system, you can create tables that combine data listings and summary statistics

in a variety of formats. Once your table is created, you can easily export or paste it into in a word processing or spreadsheet application such as Microsoft Word or Excel.

Scripting Language

The Scripting Language included in WinNonlin Pro and Enterprise provides a batch mode to use for often-repeated analysis and quick and easy re-analysis in response to data changes, as well as comprehensive archival. You can write scripts to help automate the analyses and reports required by your company method sheets.

Input and Output Data Management

WinNonlin input and analysis output data are managed via Excel-compatible spreadsheets. The data interface allows you to create and/or modify data files using formulas and functions. Import and export of ASCII and Excel files, missing value codes, column names, column formats, cut and paste, sort, merge, and powerful editing capabilities are just a few of the features included.

Validation and Validation Kits

Pharsight's products, including WinNonlin and WinNonMix®, are widely used by pharmaceutical companies, academic and research institutions, as well as regulatory agencies. Several of these organizations have audited and approved Pharsight's software and development methods as suitable for use under their GLP, GCP, and GAMP compliance/standards. Pharsight's products are developed using standard, well-documented Software Development Life Cycle (SDLC) processes and procedures, to enable users of Pharsight's products to be GLP/GCP/GAMP

compliant. Pharsight systematically validates its products as part of its software development and delivery process.

There is more to being GLP/GCP/GAMP compliant than simply buying well-documented, well-tested, well-developed software. Compliance also requires users to validate the operation of the system within their environment and to use the software properly with written Standard Operating Procedures (SOPs).

Contact Pharsight sales (sales@pharsight.com) about the availability of the WinNonlin® Validation Suite™to validate WinNonlin in your IT environment. 21 CFR Part 11 Compliance

Pharsight works with customers to help them achieve compliance with 21 CFR Part 11 (Electronic Records; Electronic Signatures; Final Rule) regulations. The Enterprise Editions of WinNonlin and WinNonMix are initial steps toward achieving this compliance, allowing users to read PK/PD data and save analysis results directly to/from any ODBC-compliant database which is protected by user login procedures (such as an Oracle database set up by the customer IT group).

To help achieve full compliance with 21 CFR Part 11, Pharsight has developed a secure research management system designed specifically for the needs of clinical pharmacology and drug metabolism researchers. The PKS Suite uses electronic signatures and audit trails to store and manage PK/PD data and analysis results from WinNonlin, WinNonMix, NONMEM, SAS and other analysis tools.

Title

Advanced PK/PD Modeling Methodology using Phoenix WinNonlin

This advanced workshop provides an interface between analysis and modeling of PK/PD data, physiological concepts, and applications to drug development and improved pharmacotherapy. The course is a combination of lectures to provide background concepts and hands-on exercises using WinNonlin.

Day 1

Nonlinear Models (Absorption)

• Linear and nonlinear models

• 0, 1st and mixed order absorption

• Differential equations

• Issues on writing complex models

• Problems and pitfalls using differential equations

• linear and nonlinear equations

• Design issues and case studies

Nonlinear Models (Elimination)

• Capacity, time and flow, Clearance models

• Derivation of models (well stirred)

• Turnover, baseline values

• In vitro/in vivo extrapolations, Vmax and Km, Clnt

• Design issues and case studies

Hands-on exercises

Day 2

Pharmacodynamics - 1

• Steady-state models

• Kinetics of drug action

• Time delays between concentration and effect (link)

• Initial parameter estimates

• Design issues and case studies

• Hands on exercises

Pharmacodynamics - 2

• Turnover concepts I

• Constant and variable baseline

• Indirect response

• Comparing link- and indirect response models

• Peak shift

• Initial estimates

• Design issues and case studies

• Hands on exercises

Pharmacodynamics - 3

• Feedback systems

• Tolerance and rebound

• Initial estimates

• Time dependent parameters

• Turnover concepts

• Synergy

• Hands-on exercises

Day 3

Pharmacodynamics - 4

• Logistic models

• Dichotomous vs. continuous data

• Design issues and case studies

• Pharmacodynamics - 5

• Dose-response-time data analysis

• How to obtain the biophase function

• Single vs multiple dosing

• Biophase availability

• Initial parameter estimates

• Confounding factors

• Hands on exercises

Open Session

• Working with your own data

• PBPK models by means of Phoenix WinNonlin

Day 4

Extrapolation across Models and Species

• Extrapolation of PK and PD data

• Physiological time

• Dedrick plots

• Scaling multicompartment models

• Comparison of exposure

• Dose Scaling

• Fitting several species simultaneously using body weight as a covariant

• In vitro/in vivo extrapolation

• Relation to turnover of endogenous substances

• Hands-on exercises

Forecasting

• Theory

• CATD and the future

• Case studies

• Design issues and case studies

Experimental Design

• Theory

• Case studies

• Design issues and case studies

• Hands-on exercises

Demonstration of 2-stage modeling population PK. Motivation for use of Phoenix NLME.

Prerequisites The course is suitable for advanced level research scientists in the

pharmaceutical industry, regulatory agencies and contract research firm who have a minimum of five years of experience in PK/PD modeling, and qualified graduate students who want to learn more about the advanced features of Phoenix WinNonlin. Previous attendance at the intermediate level PK/PD modeling course is necessary to have a good understanding of Phoenix WinNonlin and the user model language.

Overview Overview of Modeling Tools in of Modeling Tools in Drug Development.

http://blog.learnpkpd.com/2011/05/04/winnonlin-software-review-part-1/

WinNonlin Software Review – Part 1

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 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 yourlocal Pharsight representative, or by requesting information from Pharsight.