{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T23:40:44Z","timestamp":1776210044607,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications (i.e., physiologically based biopharmaceutics modeling (PBBM)) enables mechanistic modeling from dissolution to absorption and disposition, facilitating the prediction of bioequivalence (BE) outcomes and the delimitation of the safe space. This study aims to identify the product-related parameter driving ibuprofen dissolution to upgrade an existing PBPK model, so that an in vitro safe space and virtual BE (VBE) predictions of IR ibuprofen tablets can be performed. Methods: Cmax within- and between-subject variabilities of a previous PBPK model were optimized after identifying crucial physiological parameters for ibuprofen absorption and disposition. In vitro data modeling was performed to estimate the value of the parameter driving ibuprofen dissolution. A safe space was defined for this parameter and the sample size to declare BE was calculated. Finally, VBE simulations were performed to explore the effect of sample size as well as number of trial replicates and runs. Results: Cmax variability was adequately predicted after changing Vss and MRT in stomach and small intestine CV (%) to 10 and 150%, respectively. Particle surface pH was identified as the dissolution key parameter for ibuprofen. A safe space for test product surface pH values of 5.64\u20136.40 was defined in order to achieve a 90%CI for the Cmax ratio within the 80\u2013125% range when the reference product surface pH is 6.02. R-ibuprofen was identified as the most discriminative enantiomer. VBE studies with 24 individuals showed BE outcomes that are sensitive to the number of trial replicates and runs. Conclusions: Ibuprofen particle surface pH has been identified as the in vitro parameter governing dissolution in maleate buffer 7 mM with HCl pH 2.0 pretreatment, allowing to establish an in vitro safe space useful for calculating sample sizes and to evaluate the BE success rate through PBBM\/PBPK model-informed VBE simulations.<\/jats:p>","DOI":"10.3390\/pharmaceutics17040408","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:48:20Z","timestamp":1742824100000},"page":"408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4799-9076","authenticated-orcid":false,"given":"Javier","family":"Zarzoso-Foj","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Cuquerella-Gilabert","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-0247","authenticated-orcid":false,"given":"Matilde","family":"Merino-Sanjuan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Reig-Lopez","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3388-5023","authenticated-orcid":false,"given":"V\u00edctor","family":"Mangas-Sanju\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-6973","authenticated-orcid":false,"given":"Alfredo","family":"Garcia-Arieta","sequence":"additional","affiliation":[{"name":"Consultant for WHO Prequalification of Medicines Programme, 28080 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/cpt.1788","article-title":"MID3: Mission Impossible or Model-Informed Drug Discovery and Development? Point-Counterpoint Discussions on Key Challenges","volume":"107","author":"Krishnaswami","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/psp4.12223","article-title":"Commentary on the MID3 Good Practices Paper","volume":"6","author":"Manolis","year":"2017","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s40262-021-01045-7","article-title":"In Silico Modeling and Simulation to Guide Bioequivalence Testing for Oral Drugs in a Virtual Population","volume":"60","author":"Zhang","year":"2021","journal-title":"Clin. Pharmacokinet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/acs.molpharmaceut.0c00903","article-title":"Physiologically Based Pharmacokinetic\/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities","volume":"18","author":"Dressman","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1007\/s11095-022-03288-w","article-title":"Review: Role of Model-Informed Drug Development Approaches in the Lifecycle of Drug Development and Regulatory Decision-Making","volume":"39","author":"Madabushi","year":"2022","journal-title":"Pharm. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100015","DOI":"10.1124\/dmd.122.001036","article-title":"Real-World Application of Physiologically Based Pharmacokinetic Models in Drug Discovery","volume":"53","author":"Santos","year":"2025","journal-title":"Drug Metab. Dispos."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Reig-L\u00f3pez, J., Merino-Sanjuan, M., Garc\u00eda-Arieta, A., and Mangas-Sanju\u00e1n, V. (2022). A Physiologically Based Pharmacokinetic Model for Open Acid and Lactone Forms of Atorvastatin and Metabolites to Assess the Drug-Gene Interaction with SLCO1B1 Polymorphisms. Biomed. Pharmacother., 156.","DOI":"10.1016\/j.biopha.2022.113914"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/psp4.12907","article-title":"Regulatory Utility of Physiologically-Based Pharmacokinetic Modeling to Support Alternative Bioequivalence Approaches and Risk Assessment: A Workshop Summary Report","volume":"12","author":"Wu","year":"2023","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.xphs.2018.10.033","article-title":"Physiologically Based Pharmacokinetic Modeling in Regulatory Science: An Update From the U.S. Food and Drug Administration\u2019s Office of Clinical Pharmacology","volume":"108","author":"Grimstein","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nrd2173","article-title":"Simulation and Prediction of in Vivo Drug Metabolism in Human Populations from in Vitro Data","volume":"6","author":"Tucker","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1002\/jps.20857","article-title":"Physiologically-based Pharmacokinetic Modeling 2: Predicting the Tissue Distribution of Acids, Very Weak Bases, Neutrals and Zwitterions","volume":"96","author":"Rodgers","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1002\/jps.20856","article-title":"Physiologically Based Pharmacokinetic Modeling 1: Predicting the Tissue Distribution of Moderate-to-strong Bases","volume":"96","author":"Rodgers","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1208\/s12248-009-9099-y","article-title":"Population-Based Mechanistic Prediction of Oral Drug Absorption","volume":"11","author":"Jamei","year":"2009","journal-title":"AAPS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1208\/s12248-019-0298-x","article-title":"Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link\u2014A Workshop Summary Report","volume":"21","author":"Heimbach","year":"2019","journal-title":"AAPS J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1021\/acs.molpharmaceut.4c00202","article-title":"Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report","volume":"21","author":"Mackie","year":"2024","journal-title":"Mol. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1007\/s11095-022-03280-4","article-title":"The Use of Physiologically Based Pharmacokinetic Analyses-in Biopharmaceutics Applications-Regulatory and Industry Perspectives","volume":"39","author":"Anand","year":"2022","journal-title":"Pharm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1021\/acs.molpharmaceut.4c01148","article-title":"Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM): A Workshop Report","volume":"22","author":"Tannergren","year":"2025","journal-title":"Mol. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1208\/s12248-021-00672-z","article-title":"Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling","volume":"24","author":"Bego","year":"2022","journal-title":"AAPS J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.xphs.2021.10.017","article-title":"Physiologically Based Biopharmaceutics Modeling to Demonstrate Virtual Bioequivalence and Bioequivalence Safe-Space for Ribociclib Which Has Permeation Rate-Controlled Absorption","volume":"111","author":"Laisney","year":"2022","journal-title":"J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s11095-022-03319-6","article-title":"Physiologically Based Pharmacokinetics Modeling in Biopharmaceutics: Case Studies for Establishing the Bioequivalence Safe Space for Innovator and Generic Drugs","volume":"40","author":"Wu","year":"2023","journal-title":"Pharm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1016\/j.xphs.2022.09.003","article-title":"Utility of Physiologically Based Biopharmaceutics Modeling (PBBM) in Regulatory Perspective: Application to Supersede F2, Enabling Biowaivers & Creation of Dissolution Safe Space","volume":"111","author":"Bhattiprolu","year":"2022","journal-title":"J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rudolph, N., Charbe, N., Plano, D., Al Shoyaib, A., Pal, A., Boyce, H., Zhao, L., Wu, F., Polli, J., and Dressman, J. (2025). A Physiologically Based Biopharmaceutics Modeling (PBBM) Framework for Characterizing Formulation-Dependent Food Effects: Paving the Road towards Fed Virtual BE Studies for Itraconazole Amorphous Solid Dispersions. Eur. J. Pharm. Sci., 107047.","DOI":"10.1016\/j.ejps.2025.107047"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1002\/jps.20444","article-title":"Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ibuprofen","volume":"94","author":"Potthast","year":"2005","journal-title":"J. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1002\/jps.24519","article-title":"On the Biopharmaceutics Classification System Biowaiver of Ibuprofen","volume":"104","author":"Gordon","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/bdd.1800","article-title":"In Silico Prediction of Drug Dissolution and Absorption with Variation in Intestinal PH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen","volume":"33","author":"Tsume","year":"2012","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bermejo, M., Hens, B., Dickens, J., Mudie, D., Paix\u00e3o, P., Tsume, Y., Shedden, K., and Amidon, G.L. (2020). A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12010074"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Reig-L\u00f3pez, J., Cuquerella-Gilabert, M., Band\u00edn-Vilar, E., Merino-Sanju\u00e1n, M., Mangas-Sanju\u00e1n, V., and Garc\u00eda-Arieta, A. (2024). Bioequivalence Risk Assessment of Oral Formulations Containing Racemic Ibuprofen through a Chiral Physiologically Based Pharmacokinetic Model of Ibuprofen Enantiomers. Eur. J. Pharm. Biopharm., 199.","DOI":"10.1016\/j.ejpb.2024.114293"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1016\/j.xphs.2016.08.024","article-title":"Bridging the Gap Between In Vitro Dissolution and the Time Course of Ibuprofen-Mediating Pain Relief","volume":"105","author":"Cristofoletti","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121415","DOI":"10.1016\/j.ijpharm.2021.121415","article-title":"Level A IVIVC for Immediate Release Tablets Confirms In Vivo Predictive Dissolution Testing for Ibuprofen","volume":"614","author":"Blechar","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/00401706.1991.10484804","article-title":"Factorial Sampling Plans for Preliminary Computational Experiments","volume":"33","author":"Morris","year":"1991","journal-title":"Technometrics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1208\/s12248-020-00499-0","article-title":"Inter-Compound and Intra-Compound Global Sensitivity Analysis of a Physiological Model for Pulmonary Absorption of Inhaled Compounds","volume":"22","author":"Melillo","year":"2020","journal-title":"AAPS J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1021\/js980236p","article-title":"General Solution for Diffusion-Controlled Dissolution of Spherical Particles. 1. Theory","volume":"88","author":"Wang","year":"1999","journal-title":"J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/jps.10039","article-title":"General Solution for Diffusion-Controlled Dissolution of Spherical Particles. 2. Evaluation of Experimental Data","volume":"91","author":"Wang","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s11095-024-03688-0","article-title":"The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of Dipyridamole","volume":"41","author":"Kesharwani","year":"2024","journal-title":"Pharm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/sim.1783","article-title":"Sample Sizes for Clinical Trials with Normal Data","volume":"23","author":"Julious","year":"2004","journal-title":"Stat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1002\/jps.22472","article-title":"Investigation on the Possibility of Biowaivers for Ibuprofen","volume":"100","author":"Torrado","year":"2011","journal-title":"J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/jps.2600700104","article-title":"Dissolution Kinetics of Carboxylic Acids II: Effect of Buffers","volume":"70","author":"Mooney","year":"1981","journal-title":"J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1023\/A:1015970502993","article-title":"Dissolution of Ionizable Drugs in Buffered and Unbuffered Solutions","volume":"5","author":"Ozturk","year":"1988","journal-title":"Pharm. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1208\/s12248-021-00663-0","article-title":"Dissolution Challenges Associated with the Surface PH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling","volume":"24","author":"Hens","year":"2022","journal-title":"AAPS J."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Kollipara, S., Martins, F.S., Jereb, R., Krajcar, D., and Ahmed, T. (2024). Advancing Virtual Bioequivalence for Orally Administered Drug Products: Methodology, Real-World Applications and Future Outlook. Pharmaceuticals, 17.","DOI":"10.3390\/ph17070876"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"105170","DOI":"10.1016\/j.ejps.2019.105170","article-title":"Establishing Virtual Bioequivalence and Clinically Relevant Specifications Using in Vitro Biorelevant Dissolution Testing and Physiologically-Based Population Pharmacokinetic Modeling. Case Example: Naproxen","volume":"143","author":"Cristofoletti","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1021\/acs.molpharmaceut.4c00758","article-title":"PBBM Considerations for Base Models, Model Validation, and Application Steps: Workshop Summary Report","volume":"21","author":"Heimbach","year":"2024","journal-title":"Mol. Pharm."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/4\/408\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:59:25Z","timestamp":1760029165000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/4\/408"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,24]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["pharmaceutics17040408"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17040408","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,24]]}}}