Can PBPK Modeling Streamline Food Effect Assessments?

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is routinely used to study drug-drug interactions, replace some dedicated clinical studies, and inform product labeling. More recently, there has been increased application of PBPK models in the oral absorption field around drug product quality. Given the success of the models to characterize absorption of several orally administered drug products, a question arises whether PBPK could be used in a clinical setting to model food-drug interactions and thus streamline food effect assessments. Multiple publications have reported food effect predictions and comparisons with clinical data, primarily focusing on 2 food effect mechanisms: slowing down of gastric emptying and luminal solubilization by bile salts. Based on the available literature, this commentary proposes a workflow that PBPK model could be used to streamline food effect assessment during clinical development for different Biopharmaceutics Classification System classes.

Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

“…The application of physiologically based pharmacokinetic (PBPK) models can help the formulation scientist to further explore the impact of any formulation, physiology, or population parameter on the systemic exposure of the drug. − Sensitivity analyses can be performed to judge which parameters play a pivotal role in the absorption process. Moreover, if any formulation changes would be made during the clinical or postapproval phase of drug product development, these changes can be explored in the modeling software to directly anticipate the impact of these changes on the systemic outcome of the drug.…”

Regulatory utility of physiologically based pharmacokinetic modeling for assessing food impact in bioequivalence studies: A workshop summary report

“…It has become increasingly plausible that PBPK models can be used for assessing drug-drug interaction, dose adjustment during renal or hepatic impairments, pediatric dose adjustment, and biopharmaceutics-related assessment with notable success in new drug development. [1][2][3][4] Acceptability of these models has further been exemplified through the publication of PBPK guidances by both the FDA and European Medicines Agency in recent years. 5,6 In fact, the FDA's Office of Generic Drugs frequently uses mechanistic modeling and simulation approaches to support regulatory decisions.…”

“…Several studies have shown the application of oral PBPK models for assessing food impact 16–23 . In addition, some reports have also pointed out the prospects and challenges related to the use of PBPK for assessing the impact of food 1,24 . However, there still exists a knowledge gap regarding the appropriate development, validation, and use of PBPK modeling approaches for food effect assessment, specifically for regulatory submission purposes.…”

“…On the second day of this workshop, a session (Session 2) titled “Oral PBPK for Evaluating the Impact of Food on BE” was organized to present and discuss the utility and prospect of physiologically based pharmacokinetic (PBPK) modeling approaches to support fed bioequivalence (BE) studies. It has become increasingly plausible that PBPK models can be used for assessing drug–drug interaction, dose adjustment during renal or hepatic impairments, pediatric dose adjustment, and biopharmaceutics‐related assessment with notable success in new drug development 1–4 . Acceptability of these models has further been exemplified through the publication of PBPK guidances by both the FDA and European Medicines Agency in recent years 5,6 .…”

Role of Physiologically Based Pharmacokinetic Modeling and Simulation in Enabling Model‐Informed Development of Drugs and Biotherapeutics

“…The analysis suggested that PBPK models developed based on in vitro solubility, permeability, and dissolution in conjunction with PK data under fasting conditions may be a useful tool to assess food effect; however, factors such as the effect of food on the activity of enzymes and transporters and differences in how various physiological processes are parameterized across software platforms hinder the widespread application of PBPK for prospective food‐effect evaluation. In this supplement, Kesisoglou further explores if PBPK modeling can streamline food effect assessments 10 . In addition to a summary of advancements made in the area of using PBPK for predicting the effect of food and current knowledge gaps, a workflow to use PBPK to facilitate the assessment of food effect in drug development is proposed.…”