Preface

Welcome to the GastroPlus® Scientific Principles Guide. The collection of mathematical models and equations that are used in GastroPlus® simulate the effects of a variety of physicochemical, physiological, and formulation parameters on the absorption, distribution, and elimination (metabolism and excretion) of drugs after administration via a variety of dosage routes, and with the appropriate pharmacokinetic inputs, the plasma and tissue concentration profiles for both human and animal species. The purpose of the GastroPlus® Scientific Principles Guide is to provide basic, but thorough, descriptions of these mathematical models and equations, which, in turn, helps you understand how to use GastroPlus® efficiently and effectively.

Conventions used in the guide

The GastroPlus® Scientific Principles Guide uses the following conventions:

• A new term, or term that must be emphasized for clarity of procedures, is italicized.

• Units are not provided for any of the equations in this guide. To view the units for the inputs to an equation, refer to the GastroPlus® software.

• Data graphics/data models that have yet to be standardized are marked with the following disclaimer: Updated graphic TBD.

• Where appropriate, for consistency of presentation and to facilitate the understanding of the scientific principles detailed in this guide, the symbols/letters used to represent variables in many equations have been changed from those referenced in the literature to the symbols /letters that adhere to Simulations Plus’s internal documentation standards for GastroPlus®. To view the original symbol/letter for a variable, refer to the appropriate referenced manuscript.

• Because you can view this guide online, then if information appears in blue, it is a hyperlink. Table of Contents entries are also hyperlinks. Click the hyperlink to advance to the referenced information.

Organization of the guide

To facilitate comprehension of the mathematical models and equations that are detailed in this guide, the information is organized based on the pharmacokinetics principles of absorption, distribution, and elimination (metabolism and excretion). Additional chapters and appendices address related topics, including pharmacodynamics, drug-drug interactions, in vitro and in vivo correlations, and virtual bioequivalence.

In addition to this Preface, the GastroPlus® Scientific Principles Guide contains the following sections and appendices:

• AssessmentsPlus™ details the capabilities of a modeling tool within the GastroPlusGPT™ suite, designed to help GPX users build high-quality PBPK/PBBM models. It analyzes compound properties and simulation results to provide targeted feedback and improvement suggestions.

• The Advanced Compartmental Absorption and Transit Model details the Advanced Compartmental Absorption and Transit (ACAT) model developed by Simulations Plus. The chapter then details the scientific principles behind the implementation of the ACAT model to simulate the effects of a variety of physicochemical, physiological, and formulation parameters on the absorption of drugs in the gastrointestinal (GI) tract.

• Pharmacokinetics details the PBPKPlus™ module that Simulations Plus developed for the simulation of physiologically-based pharmacokinetics (PBPK) of drug candidates. It also details the use of a compartmental PK model to carry out one-, two-, or three-compartmental pharmacokinetic simulations of drug candidates.

• Pharmacodynamics details the scientific principles behind the implementation of the optional PDPlus™ module that Simulations Plus developed for modeling multiple PD effects for any drug record in a database.

• Drug-Drug Interaction Module details the optional Drug-Drug Interaction (DDI) module that Simulations Plus developed for the investigation and prediction of DDIs. The module extends the capabilities of GastroPlus® to predict competitive and/or time-dependent drug-drug interactions.

• In Vitro and In Vivo Correlation Plus Module details a Level A IVIVC, which is a specific category of IVIVC that you can carry out in the optional In Vitro and In Vivo Correlation Plus (IVIVC™) module. The IVIVC™ module was developed by Simulations Plus for carrying out different types of IVIVC correlations. You can build both conventional and mechanistic IVIVCs in this optional module.

• The Population Simulator Mode and Virtual Bioequivalence details the Population Simulator feature in GastroPlus®. You use the Population Simulator to generate realistic populations of subjects that are either healthy or that have other characteristics. You can then use population simulations in the Virtual Bioequivalence (VBE) run mode to conduct VBE trials, where VBE is defined as the demonstration of bioequivalence (BE) using modeling and simulation in lieu of clinical studies.

• Additional Dosage Routes details the Additional Dosage Routes Module (ADRM), which currently includes intramuscular drug delivery, for simulation of drug delivery in the muscle.

• Equation Standards details the internal standards that were used to define many of the equations in the GastroPlus® Scientific Principles Guide.

• Additional Suggested Reading details the references that were used in the development and validation of GastroPlus® but were not cited directly in this guide.