The Phoenix Reporter

A Compendium of Insightful Information for Our Phoenix Community – Vol. 1

Welcome to the inaugural issue of The Phoenix® Reporter. In this e-newsletter we will share informative educational content along with practical, implementable resources with our Phoenix user community.

In this issue:

  1. What’s New in Phoenix
  2. Using In Vitro-In Vivo Correlation (IVIVC) to Attain Biowaivers
  3. Learn more about Phoenix Modeling Language (PML)

What’s New in Phoenix

The New Graphics Engine

The new graphics engine automatically generates high resolution (up to 1200 dpi) publication-quality plots, figures and well-organized tables to help create standardized PK/PD reports and presentations more efficiently, eliminating the need to use third-party graphing tools. New report-ready plotting features include:

  • Customizable legend placement
  • X-categorical plots include the ability to include error bars and offsets
  • Visual Predictive Check (VPC) with shading of secondary quantiles

Phoenix Workbench Enhancements – Data Layer and Parallel Compute Technology

The new data layer delivers 90% reduction in memory utilization resulting in improved stability when working with large amounts of data or modeling projects. The WinNonlin® engine has been enhanced using parallel computing technology to conduct NCA analyses in half the time as the previous version of Phoenix. Since NCA is the first and most commonly used technology to analyze pharmacokinetic data, doubling the speed of analysis is of tremendous value to all WinNonlin users.

Want to learn more? Check out our scientific webinar that focuses on the new graphics engine and Phoenix workbench enhancements or get a high level overview of all new features in Phoenix 7.0 in a webinar given by Dr. Nathan Teuscher.

In our next issue we will highlight first-in-class cloud support for PK/PD modeling with Phoenix NLME and Integrated Differential Equation (DDE).


Using In Vitro-In Vivo Correlation (IVIVC) to Attain Biowaivers

In vitro in vivo correlation (IVIVC) is a predictive mathematical tool used in biopharmaceutical drug development and formulation optimization that describes the relationship between an in vitro property of a drug dosage form and an in vivo pharmacokinetic (PK) response. Most importantly, IVIVC is a surrogate for in vivo bioavailability and can be used to demonstrate virtual bioequivalence (BE) and support attaining regulatory biowaivers.

What is a biowaiver and why is it valuable in drug development and manufacturing?

A biowaiver is an exemption given to a pharmaceutical/biopharmaceutical company by a regulatory agency to show bioequivalence (BE) to a product as it advances through its life cycle, eg, changes in formulation, shelf life, manufacturing raw materials and supplies, dose form, and process changes. These changes would require determination of bioequivalence but the use of IVIVC has become a proven method used by drug development and formulation scientists to understand how dissolution parameters affect in vivo drug performance. The US FDA, EMA, PMDA and other global regulatory agencies encourage the use of IVIVC and view it as an important tool in drug development. IVIVC can be used as a surrogate for in vivo BE studies by providing a method to enhance product and process understandings with the ultimate goal of ensuring consistent performance throughout a product’s life cycle. Using IVIVC in drug development, formulation, and manufacturing can streamline the development process helping companies recognize a significant cost and time savings benefit.

What types of IVIVC methods are used in drug development, formulation, and manufacturing?

The IVIVC model has been defined by the Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in vitro property of a dosage form and an in vivo response.” IVIVC can be performed using conventional and complementary mechanistic-based approaches. In conventional IVIVC, the in vitro data used is the rate of drug dissolution over time. The in vivo dissolution is plotted against the in vitro dissolution using deconvolution methods to evaluate in vivo release and delivery when data from a known drug input (UIR) from IV or oral solution is available. Deconvolution methods include Wagner-Nelson, Loo-Riegelman, and Numerical, a well-documented method known for its stability and accuracy that has shown to be less susceptible to study design variation.


In a recent survey, we asked leading pharma companies to comment on preferred IVIVC methodology. The results show the benefits of both the conventional and mechanistic tools, and affirm the benefits of both for regulatory, drug development, and formulation.

Read the brochure to learn more >


Mechanistic IVIVC is a complementary approach to conventional methods and is increasingly gaining interest from regulatory agencies. In this approach, physiologically-based PK (PBPK) is leveraged to consider and separate the various mechanisms involved in absorption, such as transit time, gut wall permeability, and hepatic first-pass metabolism from dissolution rate. By integrating the anatomical and physiological parameters of the GI tract with the physiochemical properties of drug substances, mechanistic IVIVC holds great promise for designing and evaluating the performance and safety of new drug formulations.

Certara provides solutions for both a conventional and mechanistic IVIVC approaches. To learn more of our software solution for conventional IVIVC, visit Phoenix IVIVC Toolkit™, and Simcyp® Simulator for details using a mechanistic PBPK methodology.

For a comprehensive list of resources and materials that provide additional education and information on IVIVC be sure to visit the Resources section of this newsletter.


Phoenix Modeling Language (PML) School

Phoenix WinNonlin uses PML to encode pharmakokinetic (PK) and pharmacodynamic (PD) models. Although most models can be built using the graphical user interface (GUI) in Phoenix, there are some models that require custom coding with PML.

A challenge we hear from our users is the difficulty they experience in being able to learn about PML programming from either the internet or other users. We’ve recently introduced a new program of complementary educational webinar tutorials on Phoenix Modeling Language (PML) covering a range of topics. Read more about the PML series and join us for upcoming sessions.


Tips of the Trade

The most popular session during our Phoenix roadshows and customer educational sessions are Tips and Tricks in Phoenix. Today’s tip – a case study that reviews how to develop a custom IVIVC model in Phoenix. Learn More >


Resources

Following is a compendium of scientific articles and information to augment your development, manufacturing, and regulatory knowledge on IVIVC.

The Regulatory Perspective

  1. N Teuscher and N Patel. Modeling & Simulation for Drug Development & Formulation. Contract Pharma. March 7, 2017.
  2. S Suarez-Sharp, M Li, J Duan, H Shah, and P Seo. Regulatory Experience with In Vitro-In Vivo Correlations (IVIVC) in New Drug Applications. The AAPS Journal (2016). 18 (6): 1379-1390.
  3. S Suarez-Sharp, PR Delyadia, A Dorantes, J Duan, A Externbrink, Z Gao, T Ghosh, SP Miksinski, and P Seo. Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications. The AAPS Journal (2016). 18 (3): 578-588.
  4. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Guidance for the Industry. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. May 2015.
  5. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Guidance for the Industry. Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. September 1997.
Blog Posts

Upcoming and Archived Webinars

Community Forum

Become a member of the Phoenix Forum, a site dedicated for our Phoenix software community. In the forum, members can pose questions to our experts and interact with their peers – it is an excellent source to gain and share knowledge, experience and ideas. The forum is also a site to download software, check on licensing, and submit Phoenix software support requests. When you join, you can search for specific topics of interest – for example, a search on IVIVC reveals a recent post that discusses Plotting Fabs vs Fdiss using the IVIVC Toolkit.

Resource Library

Your source for all Certara information including case studies, white papers, blog posts, webinars, articles, posters, brochures and press releases. Visit the Library >

Recent IVIVC Brochures from Certara:


Learn from the Best

Become a “Most Valuable Player” by enrolling in a Certara University pharmacometrics course:
8 modeling and simulation course topics
On-site courses given in over 15 cities
On-demand, e-learning course library
See the full schedule >
We've recently introduced a new program of complementary webinar-tutorials on Phoenix Modeling Language (PML). Join our instructors and guest lecturers for this educational webinar series featuring topics submitted to our Phoenix Forum by users interested in developing custom PK/PD models.

Upcoming PML School Presentations
Analysis and Comparison of Link, Turnover and Receptor Binding Models
March 16, 2017
10am EST
Presenter: Dan Weiner
Sigmoidal Concentration-response Models
March 30, 2017
10am EST
Presenter: Chris Mehl
Analysis of a Tissue Growth/Kill Model
April 13, 2017
10am EST
Presenter: Bernd Wendt
See the full schedule and learn how to access prior tutorials >
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