{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:39:46Z","timestamp":1790008786432,"version":"4.0.1"},"reference-count":27,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"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>Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega\u00ae) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing frequency. The administration of the ER after a high-fat\/high-calorie meal leads to increased maximum plasma concentration and area under the curve values by 60% and 54%, respectively. Food has various effects on gastrointestinal (GI) physiology, including changed transit times, changed volumes, altered pH in different GI compartments, secretion of bile salts, and increased hepatic blood flow. This may affect solubility, the dissolution rate, absorption, and the pharmacokinetics. The aim of this study was to apply physiologically based absorption modeling (PBAM) to provide insights on paliperidone ER absorption under fed and fasting conditions. The PBAM adequately predicted absorption from the OROS formulation under both conditions. Absorption primarily occurs in the ascending colon and caecum. After a high-fat\/high-calorie meal, absorption is increased through the jejunum, ileum, and colon due to either increased solubilization or the better efficiency of the OROS technology. PBAM-guided approaches can improve the understanding of branded drugs and thereby aid in guiding the development of generic formulations or formulation alternatives.<\/jats:p>","DOI":"10.3390\/pharmaceutics15020629","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T05:25:26Z","timestamp":1676265926000},"page":"629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Leveraging Physiologically Based Modelling to Provide Insights on the Absorption of Paliperidone Extended-Release Formulation under Fed and Fasting Conditions"],"prefix":"10.3390","volume":"15","author":[{"given":"Saima","family":"Subhani","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA"},{"name":"Simulations Plus, Lancaster, CA 93534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viera","family":"Lukacova","sequence":"additional","affiliation":[{"name":"Simulations Plus, Lancaster, CA 93534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaejin","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1688-7008","authenticated-orcid":false,"given":"Leyanis","family":"Rodriguez-Vera","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Muniz","sequence":"additional","affiliation":[{"name":"Model Informed Development, CTI Laboratories Spain, Derio, 48160 Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0403-9810","authenticated-orcid":false,"given":"Monica","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Model Informed Development, CTI Laboratories Spain, Derio, 48160 Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Van Os","sequence":"additional","affiliation":[{"name":"Synthon BV, 6545 CM Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6683-4847","authenticated-orcid":false,"given":"Elena","family":"Suarez","sequence":"additional","affiliation":[{"name":"Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Department of Pharmacology, School of Medicine and Nursing, University of the Basque Country UPV\/EHU, 48940 Bizkaia, Spain"},{"name":"Biocruces Health Research Institute, 48903 Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4998-1167","authenticated-orcid":false,"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2636-1889","authenticated-orcid":false,"given":"Valvanera","family":"Vozmediano","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and System Pharmacology at Lake Nona (Orlando), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105812","DOI":"10.1016\/j.ejps.2021.105812","article-title":"Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review","volume":"162","author":"Vinarov","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ejps.2019.04.003","article-title":"The mechanisms of pharmacokinetic food-drug interactions\u2014A perspective from the UNGAP group","volume":"134","author":"Koziolek","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_3","unstructured":"(2023, January 23). Guidance for Industry: Assessing the Effects of Food on Drugs in INDs and NDAs\u2014Clinical Pharmacology Considerations, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/assessing-effects-food-drugs-inds-and-ndas-clinical-pharmacology-considerations."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s40268-015-0092-x","article-title":"Comparative Pharmacology of Risperidone and Paliperidone","volume":"15","year":"2015","journal-title":"Drugs R"},{"key":"ref_5","unstructured":"(2023, January 20). Invega (Paliperidone) Extended Release Tablet-Highlights of prescribing information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2010\/021999s018lbl.pdf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1124\/dmd.107.018275","article-title":"Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans","volume":"36","author":"Vermeir","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_7","unstructured":"FDA (2022, March 03). Paliperidone-New Drug Application: Amendment-Clinical Pharmacology and Biopharmaceutics Review (Application No. 21-999), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2009\/021999Orig1s004.pdf."},{"key":"ref_8","unstructured":"(2022, March 03). Invega-Paliperidone-Scientific Discussion. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-discussion\/invega-epar-scientific-discussion_en.pdf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.tibtech.2021.10.001","article-title":"Osmotic-controlled release oral tablets: Technology and functional insights","volume":"40","author":"Ogueri","year":"2022","journal-title":"Trends Biotechnol."},{"key":"ref_10","unstructured":"(2022, March 03). Enhanced Efficacy Benzisoxazole Derivative Dosage Forms and Methods. Available online: https:\/\/patents.google.com\/patent\/WO2007050377A1\/en."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1111\/jphp.12059","article-title":"Coupling biorelevant dissolution methods with physiologically based pharmacokinetic modelling to forecast in-vivo performance of solid oral dosage forms","volume":"65","author":"Otsuka","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1185\/030079906X132613","article-title":"Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form","volume":"22","author":"Conley","year":"2006","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Senekowitsch, S., Schick, P., Abrahamsson, B., Augustijns, P., Gie\u00dfmann, T., Lennern\u00e4s, H., Matthys, C., Marciani, L., Pepin, X., and Perkins, A. (2022). Application of In Vivo Imaging Techniques and Diagnostic Tools in Oral Drug Delivery Research. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040801"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ejpb.2018.05.024","article-title":"Use of biorelevant dissolution and PBPK modeling to predict oral drug absorption","volume":"129","author":"Kaur","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ejps.2013.09.006","article-title":"Quantitative prediction of formulation-specific food effects and their population variability from in vitro data with the physiologically-based ADAM model: A case study using the BCS\/BDDCS Class II drug nifedipine","volume":"57","author":"Patel","year":"2014","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.xphs.2018.11.034","article-title":"Biopharmaceutic IVIVE-Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation into PBPK Models","volume":"108","author":"Pathak","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1208\/s12248-021-00601-0","article-title":"Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models","volume":"23","author":"Wagner","year":"2021","journal-title":"AAPS J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cheng, L., and Wong, H. (2020). Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12070672"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1208\/s12248-020-00508-2","article-title":"Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: An Industry Perspective","volume":"22","author":"Riedmaier","year":"2020","journal-title":"AAPS J."},{"key":"ref_20","unstructured":"FDA (2023, January 23). Guidance for Industry the Use of Physiologically Based Pharmacokinetic Analyses\u2014Biopharmaceutics Applications for Oral Drug Product Development, Manufacturing Changes, and Controls, Available online: https:\/\/www.fda.gov\/media\/142500\/download."},{"key":"ref_21","unstructured":"Prabhakar, D., Divya, A., Prathyusha, R., and Kumar, K.S. (2022, February 28). Augmentation of Dissolution Profile of Poorly Soluble Paliperidone by Employing Liquisolid Technology. Available online: https:\/\/sphinxsai.com\/2014\/PTVOL6\/PT=39(710-719)AJ14.pdf."},{"key":"ref_22","unstructured":"(2022, January 10). Product Monograph\u2014Invega\u00ae Paliperidone Extended-Release Tablets (3 mg, 6 mg, 9 mg and 12 mg). Available online: https:\/\/pdf.hres.ca\/dpd_pm\/00043904.PDF."},{"key":"ref_23","unstructured":"(2022, January 10). PubChem Compound Summary for CID 115237, Paliperidone, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Paliperidone."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1208\/s12248-009-9087-2","article-title":"Role of physiological intestinal water in oral absorption","volume":"11","author":"Sutton","year":"2009","journal-title":"AAPS J."},{"key":"ref_25","unstructured":"Rossenu, S., Crauwels, H., and Cleton, A. (November, January 29). Comparison of the pharmacokinetics of an oral immediate-release and extended-release formulation of paliperidone in healthy subjects. Presented at the Annual Meeting and Exposition of the American Association of Pharmaceutical Sciences (AAPS), San Antonio, TX, USA."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1002\/hup.1132","article-title":"Single-dose pharmacokinetics of paliperidone extended-release tablets in healthy Chinese subjects","volume":"25","author":"Si","year":"2010","journal-title":"Hum. Psychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1177\/0091270009339190","article-title":"Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release","volume":"49","author":"Boom","year":"2009","journal-title":"J. Clin. Pharm."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/2\/629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:33:15Z","timestamp":1760121195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/2\/629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,13]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["pharmaceutics15020629"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15020629","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,13]]}}}