ConnectPAGE2012 - Certara

6/7/2012

Certara 2012 All Rights Reserved

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© Certara, L.P. 2012 All Rights Reserved

Phoenix Connect : a platform for Pharmacometrics

Modelling discussion forum: www.pharsight.com/extranet

PAGE, Venice Lido, 5th June 2012


© Tripos, L.P. All Rights Reserved

Slide 2

Agenda

1) Introduction to Phoenix platform

2) Demonstration of Phoenix project with R, NONMEM, PsN and NLME nodes

3) Hands on exercise using a simple template

4) Hands on exercise with ACCP Case 1 project

5) Homework! Optional ACCP Cases 2 & 3

6) Questions

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© Tripos, L.P. 2011 All Rights Reserved Slide 3

About Certara

Scientific and technical breadth with expertise from discovery through

clinical drug development

• History of anticipating trends and introducing innovative products

and services to assist in drug discovery and development

• Tripos: software enabling life science researchers to accelerate the

identification and optimization of new compounds in the drug, chemical,

research, food, flavoring and fragrance markets

• Simcyp : software and services for the modeling and simulation of

pharmacokinetics and pharmacodynamics in virtual human populations

and virtual laboratory animals (rat, dog and mouse). The technology

allows pharmaceutical researchers to predict in vivo outcomes from

routinely generated in vitro data, to fit Simcyp models to observed

clinical data, and to assess inter-individual variability through ‘real-life’

simulations. This informs decision-making in drug development.

• Pharsight: software and services to improve the value and availability of

preclinical and clinical program data for PK/PD modeling, analysis, data

management, and reporting


Certara Solutions Span Discovery through Development

D360™

SYBYL®-X

Muse®

PKS™

Lead

Identification

Lead

Optimization

Preclinical Phase I – II - III

Phoenix® WinNonlin®

Phoenix® NLME™Phoenix® Connect™

IVIVC Toolkit™Phoenix® JMS

Trial Simulator™

Target

Identification

PredictFX

Simcyp Simulator

Benchware® 3D Explorer

Predictive Science

Informatics

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Certara = Tripos + Simcyp + Pharsight

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in silico workflow that reduces the need for costly experimental results.

Simcyp Simulator

SYBYL QSAR predicts reaction of molecule with various enzymes and transporters critical to drug absorption and metabolism.

Simcyp Input File

Output is prediction of concentration of drug in bloodstream (PK) and prediction of Drug-Drug interactions

Input is dose

regimen, exposure

and response

Output is Prediction of PK/

PD in patient populations.

Pharsight Phoenix

Input is molecular structure

Tripos SYBYL-X

In Silico Workflow

Simcyp was acquired on Feb 24, 2012. Certara’s CTO, Dr. Dan Weiner, will now

begin leading a new scientific advisory board to execute the above vision.


Phoenix Platform

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Phoenix Product Vision - Objectives

Phoenix has a rich interface that

can support multiple Projects,

Workflows, and input Data Sources.

These can be organized to form

templates which can also be stored

in the Phoenix Library so that

future projects can be analyzed

effectively and efficiently.

This session discusses how to

navigate around the Phoenix

interface.

One software platform to support

and integrate the analytic work of

all scientific collaborators involved

in Drug Development Science.

Kineticists

Pharmacologists

Toxicologist

Pharmaceutical Development

IVIVC

Clinical PK

DMPK

Clinical Pharmacologists

Biochemists


Getting started with Phoenix

WinNonlin Online Help (within software) WinNonlin User Docs (typically located at;

C:\Program Files\Pharsight\Phoenix\docs)• Getting Started Guide

• Users Guide

• Examples Guides

• Release Notes and Product notifications

Pharsight Support

http://www.pharsight.com/support/support_sflogin.php• Example projects

• FAQ and Self Knowledge Database

• Documents/Notices

• Contact Pharsight Support

User forum is live! www.pharsight.com/extranet - Get tips and discuss models with other users.

A Comparison of Phoenix™ WinNonlin® 6.0 and WinNonlin 5.2.1http://www.pharsight.com/events/eventsonline_archive.php#replay_031

Introducing Phoenix Connect™ 1.0http://www.pharsight.com/events/eventsonline_archive.php#replay_032

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Remote Computing and Phoenix PsN Plug-in

• What is Phoenix Connect and what’s new in 6.3?

• PsN Plug-in

• Tools of Choice for Population Modelers

• Compliance, Sharing and Reproducibility

• Phoenix Remote Computing

• Windows Cluster

• Linux Cluster

• PsN Plug-in

• Sun Grid Engine

• LSF Grid Engine

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Introduction: What is Phoenix Connect™?

Phoenix Connect is a compliant pipelining solution that

integrates commonly used 3rd party data/tools within the

Phoenix platform.

• NONMEM, SAS, S+, R, SigmaPlot, PsN, Xpose

• ODBC/CDISC SDTM Import and Export

• PKS Access

Phoenix Connect saves time by allowing users to create “best of

breed” workflows

Phoenix Connect Supports Compliance

• Integrate with the PKS data management system for audit trail and

version control to support 21 CFR part 11 compliance.

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• Many workflows involve

several commonly used

tools.

• Accessing data and passing it

between applications is time

consuming and error prone.

• Other pipelining tools

require expert resources to

build the workflows.

• Provides a single common

environment to manage data

acquisition, data

preparation, analysis,

reporting and sharing.

Why Pharsight developed Phoenix Connect


Phoenix provides single Graphical Platform for Modeling

Phoenix

Connect

Clusters/Grid

Computing

SAS S+ R NONMEM SigmaPlotPsNXpose

Data/Code Model Files

.doc

Outputs

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Graphical Workflow Paradigm

• Robust

workflow engine

• Integrate R, S+,

NM, PsN and SAS

scripts

• Execute locally

or in remote

server/grid

Source Data

Model Files

Workflow


Phoenix 1.3 Enhancements

Phoenix 1.3 includes many enhancements to support pharmacometrics:

• PsN plug-in added to Phoenix Connect

• Log Viewer provides a live view into the execution of 3rd party scripts as they run.

• IDE of choice – RGUI, RStudio, Tinn-R, etc…

• Remote Execution of individual operational objects• Other parts of workflow are still accessible whilst running

• Select Sources – enables streamlined model setup

• Results Filters – filters results returned to Phoenix

• File Shortcuts – supports large files

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Phoenix Remote Computing Environment out of the box

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Windows Cluster

• NLME/WNL/AP

• NONMEM/PsN

• R

• SAS

Linux Clusters

• NONMEM/PsN

• R

• SAS

Grids

• PsN (utilising SGE or LSF)

• Other Tools have been customisedto run on the Grid

Phoenix Remote Computing


NM R

A B

Phoenix to Windows Cluster with JMS (whole workflow

submitted and locked)

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Windows Cluster

• NLME/WNL/AP

• NONMEM/PsN

• R

• SAS

Remote Environment

8 Core

8 Core

4 Core

6 Core

Job Queue Server Windows Cluster

M R

A B

RQS

R, NM, PsN

(could

be diff. OS)

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NM R

A B

Phoenix to Linux/Windows Cluster with RPS

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Linux/ WindowsCluster

• NONMEM/PsN

• R

• SAS

Remote Environment

8 Core

8 Core

4 Core

6 Core

Remote Queue ServerLinux/Windows

Cluster

NM


NM PsN

A B

Phoenix to Grids with RPS

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Grids • PsN

Remote Environment

8 Core

8 Core

4 Core

6 Core

Remote Queue Server

Submission Host

PsN

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Conclusion

• Pharmacometrics is a valuable activity that can

positively impact drug approval and labeling.

• Significant challenges remain in implementing

pharmacometrics.

• The Pharsight PMx Workbench can help overcome many

of these challenges by providing:

• Real-time access to modeling ready data sets.

• Ability to store, share and re-use data, models and outputs.

• A graphical workflow environment that supports the most

common tools used in PK/PD modeling and simulation.

• Support for compliance, including an audit trail and version

control.


Remote Execution and PsN Plug-in Demonstration

Demonstration

Single Dose IV Bolus Study

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http://accp1.org/pharmacometrics/cssolutionnm.htm

Demonstration

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Edit> Preferences > <choose tool to configure e.g. R>

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Edit> Preferences > <PsN>

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Slide 24

Phoenix: Main Window (OperationalObject: Setup)

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Slide 25

Phoenix: Main Window (OperationalObject: Results – Plot)



Slide 26

Phoenix: Main Window (OperationalObject : Verification)

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Data in and out of R (S-plus follows same conventions)

1) The following commands create the data frame in R and return a CSV to PHX respectively. A Phoenix mapping panel will be created for each attach statement and expected column names are defined in the remark #WNL_IN xxx yyyzzz #

attach(df) #WNL_IN ID AMT TIME DV MDV EVID #

nm_ready <-write.table(df,"nm_ready.csv", quote = F, sep = ", ", na= ".", row.names = F)

2) Select sources button - to point to a shortcut,< include the statement #PHX_SHORTCUT(Residuals) >

text, worksheet, or other output from previous run; the R script will need to expect the correct variable names

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Mapping panel for an R dataframe

Note res and pred are the expected variables and will map automatically if the source worksheets

variable names match, otherwise simply remap your desire input.

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Select Sources (remember Xpose needs TextOutput for header)

Note that no mapping panel is presented29


PsN plug-in contains integral scripted code builder

1)

2) Shortcuts simply point to an existing file and will

require the R script expects the correct variable

names

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PsN mouse over options will display context help

1)

2) Shortcuts simply point to an existing file and will

require the R script expects the correct variable

names

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Data in and out of NONMEM

1) For NONMEM Phoenix Connect reads the Input statement and builds the mapping panel from that;

$INPUT ID TIME CONC=DV AMT DOSE MDV

2) File > Custom import > File Shortcut from the menu bar simply point to an existing control or data file (no mapping file is created)

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Data in and out of SAS

1) Libname statements in SAS can create a Phoenix mapping panel will be created for each required dataset, the expected column names are defined in the remark #WNL_IN xxx yyy zzz # e.g.

libname indata XPORT "Final_Pa.xpt"; /*WNL_IN Subject auclast tmax cmax lambda_z hl_lz*/

proc copy in=indata out=Work;

run;

libname outdata4 XPORT "finpar.xpt";

proc copy in=work out=outdata4;

select finpar;

run;

2) Shortcuts simply point to an existing file and will require the SAS script to expect the correct variable names

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Hands on Session

1) Demonstration of re-using a

simple workflow template to

get a feel for the Phoenix

environment

2) Explore ACCP case study 1;

Single Dose IV Bolus Study

3) Use ACCP Case Studies 2 & 3 or

your own projects

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File>Import in the File menu and browse to select Noitol2.xls

View of original file in Excel, we will use the Data Wizard

options to indicate

• Data starts on Row 3. (note – blank rows are NOT presented in this preview)

• Header columns are present.

• Unit rows are present

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Sources and Data Links

External Source

Data Link

Internal Source


Why use a Data Link?

Map new Input Data only Once into the Data Link vs. Mapping the SAME Input Data to Multiple

Operational Objects in the Workflow.

Tip: Create data link so the

worksheet is only linked to data

links. If you delete the input

from the data link, downstream

objects will still be mapped to

the correct columns.

Add/remove the columns and

then re-map to the data link.

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Templates

•Only one object is required for creation of a template

•Create a template with as many objects as you want• For Example, create a template with a workflow, e.g. plot, model, table)

•Apply the template to another dataset/project

•When reapplying templates, source data are not retained, and remapping may

be required if datasets do not have similar column header names. • It is recommended that the column header names and units match those of the data worksheet

that was used to create the template

•Saved Templates have an .wnlt file extension.

To create a Template, must use the ‘Export’ feature, and select to Save as Type: WinNonlin Template (*.wnlt)


Reusing a Template

Drop new data here. Notice that

the Data Link in the template

retained information on which

External Sources (e.g. worksheet

‘EX1’) were used when the

template was created.

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File > Import from the menu bar and import graphs.WNLT

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F7 to execute a workflow

Automatic mapping when they can be matched by name

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Questions ?Simon Davis

Senior Scientific

Consultant

Mobile: +44 7980 832 [email protected]

www.pharsight.com


Pharsight PMx Workbench Screenshots

References:

1. US Food and Drug Administration. http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/UCM077258.pdf J.Clin Pharmacology, 2010; 50:9S-19S

2. Clinical Pharmacology and Therapeutics, Volume 82 Number 1 July 2007.

Impact of Pharmacometrics on Drug Approval and Labeling Decisions: A Survey of 42 New Drug Applications. Submitted: 4 April 2005; Accepted: 29 April; Published: 7 Oct 2005

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GSK/Pharsight Poster Presented at ACOP

Title: Streamlining Pharmacometric Analyses Utilizing Multiple Data Management and Modeling Tools

Authors: Samer Mouksassi*(1), Martin Beliveau (1), Erin Guinan(1), Helen Moore(1), Roberto Gomeni(2),

Xiaobin Li(2), Oscar Della Pasqua(2), Daniel Weiner(1), Frank Hoke (2)

Institutions: (1) Pharsight, Saint Louis, MO, USA; (2) Clinical Pharmacology Modeling and Simulation,

GlaxoSmithKline.


Import Multiple File Types

• Data Files

• NONMEM ctl

• R scripts

• Text/Word

Docs

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View Data Grid

Select Data File

in Object

Browser to

View Data


View Code Files

Select Code

File in Object

Browser to

View Code

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PKS Global Model/Script Library

•Global model

and script library

• Filter by meta

data

• Load workflow

to project

• Version control,

audit trail,

security, locking


PMX Workflow Engine

• Robust

workflow engine

• Integrate R, S,

NM, SAS scripts

• R script to PsN

• Execute locally

or in remote

server/grid

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NONMEM Operational Object

• NONMEM

Control File

mapping


NONMEM Operational Object

• NONMEM

Results

• Parsed results

• Graphs auto-

generated

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Xpose GoF/Individual plots

• Xpose object in

workflow

• Script from

code folder

• SDTAB1 from

NM run

• GoF plots

generated

• Indiv plots

generated


PsN Visual Predictive Check

• Xpose Setup:

Data, R Script,

Input NM ctl files

• Data Mapping

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• R Script details

• 3 VPC runs

using PsN



• Xpose VPC

results

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PsN Bootstrap with Xpose

• Bootstrap

results plotting

with Xpose


Add Workflows to Global Library

• Easy to save

workflows and

scripts to PMW

Global Library

• Workflow

Templates saved

with test data

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Integration with PKS

• Tight

integration with

PKS

• Save/Load

projects to PKS


Extendable Plug-in Architecture

• PHST and

Clients can build

plug-ins using the

Phoenix

Architecture

• Plug-ins display

in object browser

for inclusion in

workflows

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Web-based Access

• Web-based

access to model

library

• Filter on meta

data

• Assign data set

and run

workflows on

remote servers vi

web browser