The IVIVC Toolkit™ for WinNonlin - Pharsight

The IVIVC Toolkit for 

WinNonlin®: Product 

Introduction and 

Demonstration 

Jason Chittenden 

Product Marketing Manager 

All contents Copyright ©2006 Pharsight Corporation. All rights reserved. This presentation may only be viewed for personal 

use. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, 

including photocopying, for any purpose, without the express written permission of Pharsight Corporation. Pharsight®, 

WinNonlin®, IVIVC Toolkit for WinNonlin, WinNonlin AutoPilot, WinNonMix®, Pharsight Knowledgebase Server, 

PKS, PKS Reporter, Drug Model Explorer®, DMX®, Trial Simulator and TS2 are trademarks or registered trademarks of 

Pharsight Corporation. All other brand and product names are trademarks or registered trademarks of their respective holders.

About Our Presenter 

• Jason is a graduate of: 

– California State Polytechnic University in Pomona 

• B.S. in Chemical Engineering 

– University of California at Irvine 

• M.S. in Biochemical & Chemical Engineering 

• Previously: 

– Simulation Sciences- Senior Engineer 

– Alliente- Software Development Engineer 

– Simulations Plus- Senior Scientist / Product Manager for GastroPlus 

• At Pharsight: 

– Product Marketing Manager 

– Located in Cary, NC 

25 October 2006 

2 

© 2006 Pharsight Corporation. All rights reserved.

Welcome 

• About today’s audience: 

– Pharmacokineticists 

– Formulators 

– Pharmacologists 

– Quality Assurance 

– Academics 

– Managers, Directors, CEOs 

• Flow of Discussion 

– WinNonlin 

– IVIVC Toolkit 

– Sample Problem 


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What is WinNonlin? 

• Industry leading PK/PD data analysis tool 

• Intuitive and easy-to-use spreadsheet style interface 

• Powerful and fast algorithms 

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

– Three methods for AUC calculation: linear trapezoidal, linear/log trapezoidal, and linear up/log down 

– Model Fitting / Parameter Estimation 

• Extensive built-in library of predefined models 

• User defined models 

– Deconvolution, semicompartmental modeling, nonparametric superposition, crossover design, 

bioequivalence 

– Analysis using general linear modeling approaches and ANOVA 

– Descriptive statistics, including weighted descriptive statistics 

• Flexible data management 

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

– 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® 

– Units definition and conversions, including the ability to specify preferred output units, units for a dosing 

regimen, and unit conversions 

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


4 


New IVIVC Toolkit for WinNonlin 

• Extension of WinNonlin functionality 

• Separately licensed 

• Stand-alone tools enable IVIVC workflows 

– Deconvolution 

• Numerical 

• Wagner-Nelson 

• Loo-Riegelman 

– Convolution 

– Levy Plot 

• IVIVC Wizard facilitates particular IVIVC workflow 


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• IVIVC Wizard: Two-stage IVIVC development 

– Polyexponential UIR from IV or IR data 

– Deconvolution over individual subjects 

– Arbitrary IVIVC models could include 

• Dose non-linearity 

• Absorption window 

• Time scaling, shifting 

– New Convolution functionality 

– Levy plot 

– Internal and External Validation of IVIVC model 

• Convenience 

– Save settings for sharing between colleagues 

– Make a change in base data and refresh the entire analysis 


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Game Plan 

• Dissolution Data 

– Choose data to model, data for external validation 

– Select a formulation as a target (to compare to prediction) 

– We will interpolate using a dissolution model 

• Study Data 

– Use reference formulation to get Unit Impulse Response (UIR) 

– Deconvolve PK profiles using UIRs to get average fraction absorbed for each 

formulation 

• Build Correlation 

– Analyze Levy and Correlation plots to learn about possible correlation structure 

– Select and fit a correlation model 

• Evaluate Correlation Model 

– Examine prediction errors for Cmax and AUC 

• Predict 

– How similar is a new formulation to our target? 


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In Vitro Data 

Dissolution Profiles of CR formulations 

1.2 

1.0 

0.8 

0.6 

0.4 

Form=CR1 

Form=CR2 

Form=CR3 

Form=CR4 

Form=CR5 

Form=CR6 

Form=CR7 

0.2 

0.0 

0 2 4 6 8 10 12 14 16 18 

Time (h) 


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In Vivo Data 

Average PK Profiles for CR Formulations 

700 

600 

500 

400 

300 

200 

Form=CR1, Study=Study 1 







100 

0 

0 5 10 15 20 25 30 

Time (h) 


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In Vivo Data 

Average PK Profiles for Reference Formulation 

1000 

900 

800 

700 

600 

500 

400 

300 

Form=ref, Study=Study 1 




200 

100 

0 

0 5 10 15 20 25 30 

Time (h) 


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IVIVC Wizard: In-Vitro Tab 

• Locate Workbook and Worksheet with dissolution data 

• Map dissolution data 

– One dissolution profile per formulation 

• Model dissolution data 

– Using new sigmoidal models: Weibull, Hill, Double Weibull, Makoid-Banakar 

– Can choose weighting model 

– Provides for smooth interpolation while building/running models 

• Partition formulations 

– Internal validation and modeling 

– External validation 

– Target (pivotal or brand), also used for external validation 


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IVIVC Wizard: In-Vivo Tab 

• Locate Workbook and Worksheet with study data 

• Map study data 

– Which formulation was used? 

– Which columns identify unique patients? 

• Specify reference formulation 

– Used to fit Unit Impulse Response (UIR) function 

– Dosing route (IV-bolus, IV-infusion, Immediate Release/Solution) 

• Fit UIR 

– Choose weighting 

– Choose model selection 

– Will fit polyexponential to each patients reference profile 

– With IR reference, we can fit time lag and/or strip 1 st order ka 

– With IV reference, we can use bolus or infusion 


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IVIVC Wizard: In-Vivo Tab 

• Deconvolution 

– Numerical deconvolution of each profile (that isn’t reference) using UIR for that 

subject 

– Results (Fraction Absorbed, Fabs) averaged per formulation 

– Fabs based on administered dose for that formulation 

• Using other data 

– User can provide average Fabs per formulation and UIRs per subject 

– Bypasses fitting UIR and Deconvolution 

– Must strictly adhere to specified formats 

– Why? To use WN, LR or other deconvolution approach with the IVIVC Wizard 


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IVIVC Wizard: Correlation Tab 

• Exploratory Plots 

– Correlation Plot (Fabs vs. Fdiss) 

– Levy Plot (Tvivo vs. Tvitro) 

• Correlate deconvolved Fabs with Fdiss 

– Built-in equation: Fabs = Fa*Fdiss(tscale*time-tshift)-Foffset 

• Fdiss modeled or interpolated from raw data 

• Absorption cutoff optional 

– Custom equation built on user ASCII models 

• Only using modeled Fdiss 

• Can incorporate dose 

• Validation Grid 

– Runs correlation and convolution on dissolution data 

– Shows prediction error (%,ratio) of Cmax and AUC for each formulation and 

average over all formulations (internal and external) – compared to observed 

data for each formulation. 


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IVIVC Wizard: Prediction Tab 

• Locate Workbook and Worksheet with dissolution data 

• Map dissolution data 

– One dissolution profile per formulation 

• Specify dose per formulation 

• Model Dissolution Data 

– Or use interpolated raw data (with built-in models) 

• Predict PK 

– For each test formulation 

• Run correlation 

• Convolve with UIRs from target formulation 

– Uses individual UIRs, then compares mean of each. 

• Show prediction error (%,ratio) of Cmax and AUC – compared to observed data for each 

formulation. 


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IVIVC Wizard: Project Workspace 

• Load and Save projects 

• Colored bullets highlight status of project 

– Red – not completed 

– Yellow – needs to be updated 

– Green – complete 

• Designed so Prediction Tab can be used independently 

of model development workflow 


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IVIVC Wizard: Usage Scenarios 

• Develop IVIVC 

• Assist Formulation design 

• Evaluate dissolution experiment 

• Set dissolution specifications 

• Investigate absorption 

• Explore correlation structure for 1-stage IVIVC 


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IVIVC Toolkit for 

WinNonlin® Product 

Demonstration 

To view the demonstration, 

please click on the ‘Replay 

Event Now’ link for this event, 

available on our website at: 

http://www.pharsight.com/events/ 

eventsonline_archive.php


• Benefits 

– Incrementally leverage your existing investment in WinNonlin 

– Powerful IVIVC exploration and development capability 

– Visualize the in-vitro in-vivo relationship with new plotting features 

– Improve collaboration between Clinical Development and Formulation 

– Easy application of correlations to predict PK from new in vitro data 


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Questions 

??? 

Submit questions by 

clicking on the question 

mark icon on the floating 

toolbar located on the 

lower right side of your 

screen 

Or contact Pharsight 

Sales later at 

sales@Pharsight.com

The IVIVC Toolkit™ for WinNonlin - Pharsight

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