The co-administration of oral drug products with food can lead to marked alterations in bioavailability when compared to the fasted state. These food-mediated effects carry important implications across drug development, regulatory evaluation, and clinical practice. Recent research efforts have increasingly focused on elucidating the mechanistic basis of these interactions and improving the ability to predict their occurrence. Notably, findings by O’Shea et al. indicate that over 40% of drugs approved by the FDA or the EMA exhibit significant food effects on bioavailability. Given that such variability may impact drug safety and efficacy, it is essential that medications with known food-related effects be consistently administered under either fed or fasted conditions, in accordance with clinical recommendations.

In this blog post, you’ll see how physiologically based pharmacokinetic (PBPK) modeling can predict food effects early and support regulatory decisions in bioequivalence (BE) studies. You’ll also learn how to choose the right PBPK platform for accurate, efficient assessments.

How can PBPK modeling streamline food effect assessment?

PBPK modeling is a well-established tool in drug development and is widely used to evaluate drug-drug interactions (DDIs), reduce the need for certain clinical trials, and inform regulatory labeling decisions. More recently, its application has expanded into the realm of oral drug absorption, particularly in supporting questions around product quality.

As confidence grows in the ability of PBPK models to accurately characterize the absorption of orally administered drugs, a natural question emerges: Can these models also help predict and assess food effects in a clinical context?

Emerging evidence says yes. A growing number of publications have demonstrated that PBPK models can replicate clinical food-effect data with a reasonable degree of accuracy (Pepin 2024 and Nakayama 2024). These studies often focus on two primary physiological mechanisms: the delay in gastric emptying and the enhanced solubilization of drugs in the intestine mediated by bile salts following food intake.

What makes this approach even more powerful is the ability to simulate the impact of different meal types—such as high-fat, standard, or low-calorie meals—each introducing distinct changes in gastrointestinal physiology. Using PBPK modeling for these scenarios provides valuable insights into the likelihood, magnitude, and mechanisms of food effects, well before clinical trials begin. Also, by revealing the impact of administration and dosing strategies, PBPK modeling reinforces the importance of educating both physicians and patients and can help inform prescribing information on drug labels.

Building on the available literature, a proposed workflow suggests how PBPK modeling could be integrated into clinical development to streamline food-effect evaluations, especially when considering drugs from different biopharmaceutics classification system (BCS) classes. This modeling-based approach not only enhances mechanistic understanding but also offers a path to reduce development timelines and optimize clinical study design.

Can PBPK modeling support regulatory assessment of food impact in bioequivalence studies?

Yes—and recent regulatory initiatives are actively reinforcing its potential.

PBPK is increasingly being recognized as a valuable tool for assessing the impact of food on bioavailability (BA) and BE, particularly within the context of generic drug development. This growing acceptance was the focus of a dedicated session during the FDA Center for Research on Complex Generics’ workshop, “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches.”

The experts from regulatory agencies, academia, and industry presented successful case studies and discussed how PBPK models can be applied to simulate and predict food effects in BE studies. The consensus was clear: PBPK modeling offers a mechanistic, science-driven framework that can complement or, in some cases, reduce the need for dedicated fed-state clinical trials.

The regulatory utility of PBPK is reinforced by the publication of formal guidances from both the FDA and the EMA. These guidelines acknowledge the model’s capacity to account for key physiological variables—such as gastrointestinal transit, pH, bile salt secretion, and enzyme activity—which are all influenced by food intake and critically affect drug absorption.

While the potential is strong, the workshop also highlighted ongoing challenges, such as the need for robust model validation and standardized best practices for regulatory submissions.

What should you consider when selecting a reliable PBPK platform for food effect modeling?

When considering PBPK platforms for food-effect assessments, it’s critical to evaluate how reliable predictions will be. There are a few questions to answer during your selection process that should help you identify a PBPK platform you will be confident in and trust.

• Has the platform been shown to offer accurate food-effect assessments in the past?
  GastroPlus has been validated in thousands of peer-reviewed publications over the years across all discovery/development applications, with hundreds focused on food effect predictions for different drug types and formulations—proof of the trust it has earned from pharmaceutical innovators and global regulators.
• Is the platform commercial or open source?
  Commercial software platforms like GastroPlus issue regular updates, provide training, and offer technical assistance for users. Open-source options typically cannot provide robust support when challenges arise.
• How current are the models and data used in the platform?
  Scientific knowledge is constantly growing, and to leverage it in modeling one must be using software that regularly integrates new findings. GastroPlus has active collaborations with industry partners, academic researchers, and regulatory-science groups, which feed new data and insights into the software and provide the most up-to-date and rigorously validated PBPK/PBBM capabilities for confident food assessments.

In conclusion, understanding the impact of food on drug absorption is critical to ensuring the safety, efficacy, and success of pharmaceutical products. By leveraging tools like GastroPlus, researchers can anticipate and address food-drug interactions early in the development process, ultimately improving drug design and regulatory outcomes.

If you’re looking for more insights into how PBPK models can streamline food effect assessments and optimize drug development, our team of experts is here to help. Discuss your project needs with our experts.

References:

O’Shea, J. P., Holm, R., O’Driscoll, C. M., & Griffin, B. T. (2019). Food for thought: Formulating away the food effect – a PEARRL review. Journal of Pharmacy and Pharmacology, 71(4), 510–535. https://doi.org/10.1111/jphp.12957

Nakayama S, Lukacova V, Tanabe S, Watanabe A, Mullin J, Suarez-Sharp S, Shimizu T. Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure. Clin Pharmacol Drug Dev. 2024 Apr;13(4):440-448. doi: 10.1002/cpdd.1385.

Pepin XJH, Hynes SM, Zahir H, Walker D, Semmens LQ, Suarez-Sharp S. Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling. CPT Pharmacometrics Syst Pharmacol. 2024 Oct;13(10):1771-1783. doi: 10.1002/psp4.13221.