{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:15:50Z","timestamp":1773051350378,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,8]],"date-time":"2024-06-08T00:00:00Z","timestamp":1717804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundo Europeu de Desenvolvimento Regional","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was conducted to verify what peptides have been used as adjuvants in the last decades, and it was noticed that MDP derivatives have been used, with one of them even being commercially approved and used as an adjuvant when administered intravenously in oncology. The aim of this study was to build optimized models for three MDP peptides (MDP itself, MTP-PE, and murabutide) and to verify if they could act as adjuvants for an oral vaccine. Challenges faced by peptides in an oral delivery system are taken into consideration, and improvements to the formulations to achieve better results are described in a step-wise approach to reach the most-optimized model. Once simulations are performed, results are compared to determine what would be the best peptide to support as an oral adjuvant. According to our results, MTP-PE, the currently approved and commercialized peptide, could have potential to be incorporated into an oral formulation. It would be interesting to proceed with further in vivo experiments to determine the behavior of this peptide when administered orally with a proper formulation to overcome the challenges of oral delivery systems.<\/jats:p>","DOI":"10.3390\/pharmaceutics16060780","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T10:45:56Z","timestamp":1718016356000},"page":"780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Physiologically Based Pharmacokinetic (PBPK) Study to Assess the Adjuvanticity of Three Peptides in an Oral Vaccine"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1055-3912","authenticated-orcid":false,"given":"Leonor","family":"Saldanha","sequence":"first","affiliation":[{"name":"PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"\u00dclo","family":"Langel","sequence":"additional","affiliation":[{"name":"Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia"},{"name":"Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tizard, I.R. (2021). Chapter 7\u2014Adjuvants and adjuvanticity. Vaccines for Veterinarians, Elsevier.","DOI":"10.1016\/B978-0-323-68299-2.00016-2"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100667","DOI":"10.1016\/j.ctarc.2022.100667","article-title":"A comparison of cancer vaccine adjuvants in clinical trials","volume":"34","author":"Marriott","year":"2023","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_3","first-page":"1459394","article-title":"Adjuvants: Classification, Modus Operandi, and Licensing","volume":"2016","author":"Lunardelli","year":"2016","journal-title":"J. Immunol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Facciol\u00e0, A., Visalli, G., Lagan\u00e0, A., and Di Pietro, A. (2022). An Overview of Vaccine Adjuvants: Current Evidence and Future Perspectives. Vaccines, 10.","DOI":"10.3390\/vaccines10050819"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"50795","DOI":"10.3389\/fimmu.2013.00114","article-title":"Mechanisms of Action of Adjuvants","volume":"4","author":"Awate","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1023\/A:1016104910582","article-title":"Recent Advances in Vaccine Adjuvants","volume":"19","author":"Singh","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41392-023-01557-7","article-title":"Vaccine adjuvants: Mechanisms and platforms","volume":"8","author":"Zhao","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Homayun, B., Lin, X., and Choi, H.J. (2019). Challenges and Recent Progress in Oral Drug Delivery Systems for Biopharmaceuticals. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11030129"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s40264-015-0350-4","article-title":"Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs","volume":"38","author":"Petrovsky","year":"2015","journal-title":"Drug Saf."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vogel, H.G., Maas, J., Hock, F.J., and Mayer, D. (2013). In Silico Methods. Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays, Springer.","DOI":"10.1007\/978-3-642-25240-2"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3389\/fchem.2020.00612","article-title":"Editorial: In silico Methods for Drug Design and Discovery","volume":"8","author":"Brogi","year":"2020","journal-title":"Front. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ymeth.2020.01.011","article-title":"In silico trials: Verification, validation and uncertainty quantification of predictive models used in the regulatory evaluation of biomedical products","volume":"185","author":"Viceconti","year":"2021","journal-title":"Methods"},{"key":"ref_13","unstructured":"(2024, May 04). Guideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-and-simulation_en.pdf."},{"key":"ref_14","unstructured":"(2024, May 04). Physiologically Based Pharmacokinetic Analyses\u2014Format and Content Guidance for Industry, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/physiologically-based-pharmacokinetic-analyses-format-and-content-guidance-industry."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/psp.2013.41","article-title":"Basic Concepts in Physiologically Based Pharmacokinetic Modeling in Drug Discovery and Development","volume":"2","author":"Jones","year":"2013","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.apsb.2016.04.004","article-title":"PBPK modeling and simulation in drug research and development","volume":"6","author":"Zhuang","year":"2016","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Marques, L., Costa, B., Pereira, M., Silva, A., Santos, J., Saldanha, L., Silva, I., Magalh\u00e3es, P., Schmidt, S., and Vale, N. (2024). Advancing Precision Medicine: A Review of Innovative In Silico Approaches for Drug Development, Clinical Pharmacology and Personalized Healthcare. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030332"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1016\/j.drudis.2022.04.015","article-title":"Opportunities and challenges of physiologically based pharmacokinetic modeling in drug delivery","volume":"27","author":"Wang","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Saldanha, L., Langel, \u00dc., and Vale, N. (2023). In Silico Studies to Support Vaccine Development. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020654"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.yrtph.2015.02.005","article-title":"A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant","volume":"71","author":"Tegenge","year":"2015","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lou, J., Duan, H., Qin, Q., Teng, Z., Gan, F., Zhou, X., and Zhou, X. (2023). Advances in Oral Drug Delivery Systems: Challenges and Opportunities. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020484"},{"key":"ref_22","first-page":"1157","article-title":"Structure-function investigation of glucosaminylmuramoylpeptides. Influence of chemical modification of N-acetylglucosaminyl-Nacetylmuramoyldipeptide (GMDP) on its immunomodulatory properties in vivo and in vitro","volume":"17","author":"Meshcheryakova","year":"1991","journal-title":"Bioorg. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2147\/TCRM.S5688","article-title":"Review of mifamurtide in the treatment of patients with osteosarcoma","volume":"6","author":"Kager","year":"2010","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"607178","DOI":"10.3389\/fimmu.2021.607178","article-title":"Strategies for Using Muramyl Peptides\u2014Modulators of Innate Immunity of Bacterial Origin\u2014in Medicine","volume":"12","author":"Guryanova","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2165\/11204910-000000000-00000","article-title":"Mifamurtide","volume":"12","author":"Frampton","year":"2010","journal-title":"Pediatr. Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1111\/bcp.12261","article-title":"Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment","volume":"77","author":"Venkatakrishnan","year":"2014","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","unstructured":"(2023, December 10). EMA. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/mepact-epar-product-information_en.pdf."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1517\/14656566.2011.543129","article-title":"Mifamurtide for the treatment of nonmetastatic osteosarcoma","volume":"12","author":"Ando","year":"2011","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Saldanha, L., and Vale, N. (2023). The First Physiologically Based Pharmacokinetic (PBPK) Model for an Oral Vaccine Using Alpha-Tocopherol as an Adjuvant. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15092313"},{"key":"ref_30","unstructured":"(2024, May 18). ADMET Predictor\u00ae. Available online: https:\/\/www.simulations-plus.com\/software\/admetpredictor\/."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1002\/jcc.27086","article-title":"Development and test of highly accurate endpoint free energy methods. 2: Prediction of logarithm of n-octanol-water partition coefficient (logP) for druglike molecules using MM-PBSA method","volume":"44","author":"Sun","year":"2023","journal-title":"J. Comput. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1080\/17460441.2020.1691995","article-title":"Is there enough focus on lipophilicity in drug discovery?","volume":"15","author":"Lobo","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1002\/jps.24258","article-title":"Direct In Vivo Human Intestinal Permeability (Peff) Determined with Different Clinical Perfusion and Intubation Methods","volume":"104","author":"Dahlgren","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1016\/j.apsb.2021.04.001","article-title":"Oral delivery of proteins and peptides: Challenges, status quo and future perspectives","volume":"11","author":"Zhu","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.addr.2016.01.010","article-title":"Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts","volume":"101","author":"Moroz","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/bdd.1848","article-title":"Structure-based prediction of human intestinal membrane permeability for rapid in silico BCS classification","volume":"34","author":"Sun","year":"2013","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Maher, S., Brayden, D.J., Casettari, L., and Illum, L. (2019). Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11010041"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.jsps.2014.06.004","article-title":"A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives","volume":"24","author":"Muheem","year":"2016","journal-title":"Saudi Pharm. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1097\/00126334-200207010-00005","article-title":"Clinical Tolerance and Immunologic Effects After Single or Repeated Administrations of the Synthetic Immunomodulator Murabutide in HIV-1-Infected Patients","volume":"30","author":"Amiel","year":"2002","journal-title":"JAIDS J. Acquir. Immune Defic. 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