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Open Access 03-02-2025 | Original Research Article

Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs

Authors: Karine Rodriguez-Fernandez, José David Gómez-Mantilla, Suneet Shukla, Peter Stopfer, Peter Sieger, Victor Mangas-Sanjuán, Sheila Annie Peters

Published in: Clinical Pharmacokinetics

Abstract

Introduction and Objective

Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro–in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration–time data.

Methods

A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium. The compounds were ranked from the lowest to the highest dose-adjusted FaSSIF solubility (FaSSIF/D) value and subdivided into three areas based on an upper and a lower limit: drugs with FaSSIF/D > upper limit having no FE, drugs with FaSSIF/D < lower limit having FE, and drugs between the limits said to be in the sensitivity range (SR), for which we tested the hypothesis that solubility-limited absorption (SLA) identified by simplified PBPK model can reliably predict positive FE if their exposures are not impacted by gut efflux or gut metabolism.

Results

We demonstrate, using a subset of drugs within SR for which PBPK models were available, that drugs with SLA exhibited a positive FE, while those with no SLA did not show FE.

Conclusions

This proposal allows for a reliable binary prediction of FE to enable timely decisions on the need for pilot FE studies as well as the timing of pivotal FE studies.

Graphical Abstract

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Title: Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs
Authors: Karine Rodriguez-Fernandez
José David Gómez-Mantilla
Suneet Shukla
Peter Stopfer
Peter Sieger
Victor Mangas-Sanjuán
Sheila Annie Peters
Publication date: 03-02-2025
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-025-01473-9

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Springer Medicine

Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs

Abstract

Introduction and Objective

Methods

Results

Conclusions

Graphical Abstract

Keynote webinar | Spotlight on adolescent vaping

Springer Medicine

Abstract

Introduction and Objective

Methods

Results

Conclusions

Graphical Abstract

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