Advancing Virtual Bioequivalence for Orally Administered Drug Products: Methodology, Real-World Applications and Future Outlook.

Bioequivalence studies are pivotal in generic drug development wherein therapeutic equivalence is provided with an innovator product. However, bioequivalence studies represent significant complexities due to the interplay of multiple factors related to drug, formulation, physiology, and pharmacokinetics. Approaches such as physiologically based biopharmaceutics modeling (PBBM) can enable virtual bioequivalence (VBE) assessment through appropriately developed and validated models.

The Role of Model Master Files for Sharing, Acceptance, and Communication with FDA.

With the evolving role of Model Integrated Evidence (MIE) in generic drug development and regulatory applications, the need for improving Model Sharing, Acceptance, and Communication with the FDA is warranted. Model Master File (MMF) refers to a quantitative model or a modeling platform that has undergone sufficient model Verification & Validation to be recognized as sharable intellectual property that is acceptable for regulatory purposes. MMF provides a framework for regulatorily acceptable modeling practice, which can be used with confidence to support MIE by both the industry and the U.

Using Mechanistic Modeling Approaches to Support Bioequivalence Assessments for Oral Products.

This report summarizes the proceedings for Day 1 Session 3 of the 2-day public workshop entitled "Best Practices for Utilizing Modeling Approaches to Support Generic Product Development," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) in the year 2022. The aims of this workshop were to discuss how to modernize approaches for efficiently demonstrating bioequivalence (BE), to establish their role in modern paradigms of generic drug development, and to explore and develop best practices for the use of modeling and simulation approaches in regulatory submissions and approval. The theme of this session is mechanistic modeling approaches supporting BE assessments for oral drug products.

Predictive Potential of Acido-Basic Properties, Solubility and Food on Bioequivalence Study Outcome: Analysis of 128 Studies.

Background And Objectives: Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome.

Methods: We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs.

Predictive Potential of BCS and Pharmacokinetic Parameters on Study Outcome: Analysis of 198 In Vivo Bioequivalence Studies.

Background And Objectives: Understanding predictive potential of parameters to perform early bioequivalence (BE) risk assessment is crucial for good planning and risk mitigation during product development. The objective of the present study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE study.

Methods: Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.

Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report.

For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost-prohibitive. Mechanistic modeling approaches, such as physiologically-based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues.

Evaluating the Impact of Physiological Properties of the Gastrointestinal Tract On Drug In Vivo Performance Using Physiologically Based Biopharmaceutics Modeling and Virtual Clinical Trials.

The physiological properties of the gastrointestinal tract, such as pH, fluid volume, bile salt concentration, and gastrointestinal transit time, are highly variable in vivo. These properties can affect the dissolution and absorption of a drug, depending on its properties and formulation. The effect of gastrointestinal physiology on the bioperformance of a drug was studied in silico for a delayed-release pantoprazole tablet and an immediate-release dolutegravir tablet.

Prediction of fasted and fed bioequivalence for immediate release drug products using physiologically based biopharmaceutics modeling (PBBM).

Bioequivalence studies are an integral part of clinical pharmacology strategy for drug development. Physiologically based biopharmaceutics modeling (PBBM) can be a helpful tool to assess potential bioequivalence risks and predict the outcome of bioequivalence studies. In this study, GastroPlus™ was used for virtual bioequivalence (VBE) assessment of 6 case studies which includes four BCS 2, and one each of BCS 1 and 3 molecules.

The biorelevant simulation of gastric emptying and its impact on model drug dissolution and absorption kinetics.

The highly variable physiological conditions within the gastrointestinal tract can cause variable drug release and absorption from the orally administrated dosage forms. The emptying of the gastric content is one of the most critical physiological processes, dictating the amount of the active ingredient available for absorption into the systemic circulation. In this study, we prepared two water gastric emptying regimes on advanced gastric simulator (AGS) with programmable "pyloric" valve.

In vitro-In vivo Relationship and Bioequivalence Prediction for Modified-Release Capsules Based on a PBPK Absorption Model.

A physiologically based pharmacokinetic (PBPK) absorption model was developed in GastroPlus™ based on data on intravenous, immediate-release (IR), and modified-release (MR) drug products. The predictability of the model was evaluated by comparing predicted and observed plasma concentration profiles; average prediction errors (PE) were below 10%. IVIVR was developed using mechanistic deconvolution for a MR drug product to evaluate the in vivo effect of a proposed change in dissolution specification.

PBPK Absorption Modeling of Food Effect and Bioequivalence in Fed State for Two Formulations with Crystalline and Amorphous Forms of BCS 2 Class Drug in Generic Drug Development.

Prediction of the effect of food on drug's pharmacokinetics using modeling and simulation could cause difficulties due to complex in vivo processes. A generic formulation with amorphous form of BCS 2 class drug substance was developed and compared in vitro and in vivo to the reference drug product with drug substance in crystalline form. In order to approve generic formulation, some regulatory agencies are requesting to perform bioequivalence (BE) studies also in fed state.