What is Virtual Bioequivalence (VBE)?

Bioequivalence is used to assess comparison of relative bioavailability between of two preparations of the same drug. Bioavailability is the extent at which a drug enters its intended biological destination, or systemic circulation. Bioequivalence studies are required when creating a generic drug, creating a new formulation, or switching manufacturing sites. Typically, bioequivalence is demonstrated via pharmacokinetic analysis after clinical trials.

Virtual Bioequivalence (VBE) is when bioequivalence is demonstrated using modeling and simulation in lieu of clinical studies. As per FDA, physiologically-based pharmacokinetic modeling (PBPK) can be used to inform regulatory decision-making with respect to demonstrating VBE between test and reference formulations for new and generic drugs. Additionally, VBE is now demonstrating its ability to extend BCS-based biowaivers beyond BCS Class I and III compounds in certain cases. VBE saves time, money, and gets safe drugs to patients faster than traditional bioequivalence methods.

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Simcyp Virtual Bioequivalence (VBE)

The Simcyp Simulator has been successfully applied to demonstrate VBE in a range of product types delivered orally, intravenously and dermally. Simcyp VBE has enabled:

  • Regulatory-approved waiver of BE studies
  • Verify changes in manufacturing sites and/or raw material suppliers
  • Test, evaluate and approve new product formulations and alternative drug delivery methods
  • Expedite internal decision-making, including go/no go options
  • Shift development to a more efficient, science-driven paradigm

 

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Simcyp Virtual Bioequivalence (VBE)
Unique VBE Module in Simcyp Simulator

Unique VBE Module in Simcyp Simulator

The Simcyp Simulator now features an expanded VBE module, available for licensure by Simcyp consortium members. The tool allows simulation of various VBE studies for oral and dermally applied drugs. Both crossover and parallel trial designs can be simulated. In addition, a custom BE design option enables users to define up to four sequences and four periods in each sequence. Depending upon the crossover study design (standard crossover trial design or partial or full replicate crossover trial design), each simulated individual, randomly picked up from a desired population, receives both reference and test formulations. Simulations are performed for each individual in the different periods, with both intra- and inter-individual variability defined for a selection of desired model parameters.

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First FDA-approved complex topical generic used Simcyp to prove bioequivalence

Demonstrating bioequivalence is especially complex for topical, dermatological generic treatment. Simcyp’s Mechanistic Dermal Absorption (MechDermA™) model using MPML (multi phase multi layer) approach was developed to demonstrate virtual bioequivalence (VBE). This model was used to demonstrate generic bioequivalence to FDA and gained approval in 2019 using the agency’s abbreviated new drug application pathway. This model is part of an ongoing initiative which recently gained additional funding by FDA grant. This additional investment enables similar usage for complex, multi-phase formulations and advanced drug release technologies such as microspheres and liposomes and also focus on defining best practices for in vitro data usage.

Read FDA published paper on this case study
First FDA-approved complex topical generic used Simcyp to prove bioequivalence
Bastek Photo
Sebastian Polak, PhD Senior Scientific Advisor & Head of Mechanistic Dermal Modelling

Bastek leads the development of dermal models at Simcyp and cardiac safety modeling and simulation system – Cardiac Safety Simulator. He is also a tenured Professor in Biopharmaceutics at the Faculty of Pharmacy at Jagiellonian University in Krakow, Poland.

Nikunjkumar Patel
Nikunjkumar Patel, PhD Senior Consultant and Biopharmaceutics Scientific Advisor

Nikunj has more than 11 years of experience in computer aided drug design and PKPD modelling including 8+ years of experience focusing on PBPK modelling. He joined Certara’s Simcyp division in 2011 and worked extensively on oral and dermal absorption PBPK Modelling and mechanistic cardiac safety risk assessment. He has a doctorate degree in Quantitative Systems Toxicology and Safety.

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