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Virtual Bioequivalence (VBE) & PBPK/PBBM Modeling

Model-Informed Drug Development

Introduction

Model-Informed Drug Development

PharmaPrimes provides Model-Informed Drug Development services integrating Physiologically Based Pharmacokinetic (PBPK) and Physiologically Based Biopharmaceutics Modeling (PBBM) with Virtual Bioequivalence simulations using GastroPlus®.

These approaches integrate in-vitro data, API physicochemical properties, formulation characteristics, physiological parameters, and available clinical pharmacokinetic data to support pharmaceutical development and bioequivalence strategy.

Applications

How Modeling Supports Your Program

Modeling is applied where it is scientifically relevant to the development question.

  • Formulation Optimization
  • Development Risk Assessment
  • Design and Optimization of BE Studies
  • Mechanistic Support for BCS-Based Biowaiver Strategies where applicable
  • Evaluation of Formulation Changes
  • Evaluation of Manufacturing Changes
  • Scientific Regulatory Justification
  • Investigation of OOS/OOT Findings where modeling is scientifically relevant
  • Root-Cause Analysis and CAPA Support
  • Troubleshooting Bioequivalence Failures
VBE Workflow

From Data to Decision

01

Data Collection

Potential inputs:

  • API physicochemical properties
  • pKa
  • logP
  • pH-solubility profile
  • Particle Size Distribution
  • In-vitro dissolution profiles
  • Formulation composition
  • Available clinical PK data
02

PBPK/PBBM Model Development

Integration of drug, formulation, dissolution, and physiological information into a mechanistic model.

03

Model Validation

Comparison of simulated PK profiles with appropriate observed clinical data where available.

04

Virtual Trial Simulation

Simulation of virtual populations and prediction of plasma concentration-time profiles.

05

Bioequivalence Evaluation

Statistical assessment of relevant PK parameters, particularly Cmax and AUC.

Deliverables

What You Receive

  • Model Documentation
  • Virtual Population Simulations
  • Predicted PK Profiles
  • Bioequivalence Statistical Analysis
  • Scientific Interpretation
  • VBE Assessment Report
Software

GastroPlus®

Modeling and simulation are performed using GastroPlus®.

Regulatory Framework

Regulatory Guidance Supporting Model-Informed Development

PBPK/PBBM modeling and simulation are recognized within regulatory frameworks and guidance issued by major regulatory authorities and international harmonization bodies, including the U.S. FDA, EMA, and ICH.

Model-informed approaches may support drug development, bioequivalence assessment, and regulatory decision-making when scientifically justified and applied in accordance with applicable regulatory requirements.

FDA2018U.S. Food and Drug AdministrationPhysiologically Based Pharmacokinetic Analyses — Format and ContentGuidance for IndustryOfficial source (opens in a new tab)EMA2019European Medicines AgencyGuideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and SimulationScientific guidelineOfficial source (opens in a new tab)ICH2026International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human UseICH M15General Principles for Model-Informed Drug DevelopmentOfficial source (opens in a new tab)

These references are listed for regulatory context only. They do not represent endorsement, certification, or approval of PharmaPrimes or its services by any regulatory authority.

Case Studies

VBE & PBPK Case Studies

Real-world applications of model-informed approaches in bioequivalence assessment and regulatory decision-making.

Our Success Stories · Case Study 01PharmaPrimes VBE Case Study

VBE Study for Clarithromycin 125 mg/5 mL Suspension

  • The study was designed based on the observed clinical data for the reference drug.
  • The 90% CI for Cmax was (87.89–101.92), while for the AUC0-t it was (86.221–97.154).
90% CI87.89–101.92Cmax
90% CI86.221–97.154AUC0-t

Clarithromycin Plasma Concentration

Clarithromycin plasma concentration (ng/mL, logarithmic scale from 1 to 1000) versus time (0 to 25 hr) for three series: Observed RLD, Predicted RLD and Predicted test
Observed RLDPredicted RLDPredicted test

Outcome Variables for the Clarithromycin VBE Study

ParameterObserved (reference)Predicted (reference)Observed (test)Predicted (test)Fold-difference
Cmax (ng/mL)690.45663767.8566000.96
AUC0-t (ng.hr/L)3984.54549.44383.4424141.91.14
Case Study 02Published FDA Regulatory Example

Diclofenac 1% Topical Gel – FDA

A public regulatory example of PBPK modeling applied to a bioequivalence decision. This work was not conducted by PharmaPrimes.

The U.S. FDA has reported that PBPK modeling and simulation supported the approval of a generic diclofenac sodium topical gel, 1%.

A dermal PBPK model was used to perform a virtual bioequivalence assessment based on predicted local and systemic diclofenac exposure. Together with the other evidence in the application, this was used in place of a comparative clinical endpoint bioequivalence study.

FDA describes it as the first abbreviated new drug application (ANDA) approval for which a PBPK model supported the bioequivalence assessment.

Sources
  1. U.S. FDA. How Modeling Was Used to Support the FDA Approval of a Topical Generic Drug Product.
  2. Tsakalozou E, Babiskin A, Zhao L. Physiologically-based pharmacokinetic modeling to support bioequivalence and approval of generic products: A case for diclofenac sodium topical gel, 1%. CPT Pharmacometrics Syst Pharmacol. 2021;10(5):399-411. doi:10.1002/psp4.12600
  • ProductGeneric diclofenac sodium topical gel, 1%
  • Regulatory pathwayU.S. FDA abbreviated new drug application (ANDA)
  • Modeling approachDermal PBPK model with virtual bioequivalence assessment
  • Regulatory applicationSupported the bioequivalence assessment in place of a comparative clinical endpoint study
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Regulatory Support

Scientific and regulatory support including pharmaceutical dossier assessment, CTD documentation support, scientific justification, and regulatory submission support.

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Discuss a Modeling Strategy

Tell us about your formulation, available data, and development question, and our modeling team will outline a suitable PBPK/PBBM or VBE approach.

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