{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:05:23Z","timestamp":1784610323811,"version":"3.55.0"},"reference-count":53,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Simcyp Consortium of pharmaceutical companies"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate cytochrome P450 (CYP) enzymes, reducing the metabolism of CYP substrates. Cytokine antagonists (such as IL-6 receptor antagonists) can counteract this effect, restoring CYP activity and increasing drug clearance. However, quantitative prediction of cytokine-mediated drug interactions remains challenging, as existing models often lack the mechanistic detail needed to capture the dynamic relationship between cytokine signalling, receptor engagement, and downstream modulation of drug metabolism. Methods: A physiologically based pharmacokinetic (PBPK) framework incorporating cytokine\u2013receptor binding, subsequent downregulation of CYP expression, and blockade of the cytokine signalling by a therapeutic protein antagonist was developed to simulate and investigate cytokine antagonist-drug interactions. Tocilizumab, a humanised IL-6 receptor antagonist used to treat several inflammatory conditions associated with elevated IL-6 levels, was selected as a model drug to demonstrate the utility of the framework. Results: The developed PBPK model accurately predicted the pharmacokinetics profiles of tocilizumab and captured clinically observed dynamic changes in simvastatin exposure before and after tocilizumab treatment in rheumatoid arthritis (RA) patients. Simulated IL-6 dynamics aligned with observed clinical profiles, showing transient elevation following receptor blockade and associated restoration of CYP3A4 activity. Prospective simulations with commonly co-administered CYP substrates (celecoxib, chloroquine, cyclosporine, ibuprofen, prednisone, simvastatin, and theophylline) in RA patients revealed dose regimen- and drug-dependent differences in interaction magnitude. Conclusions: This study demonstrated the utility of PBPK models in providing a mechanistic understanding of cytokine antagonist-drug interactions, supporting enhanced therapeutic decision-making and optimising patient care in inflammatory conditions.<\/jats:p>","DOI":"10.3390\/pharmaceutics17070896","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T15:19:31Z","timestamp":1752247171000},"page":"896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mechanistic Insights into Cytokine Antagonist-Drug Interactions: A Physiologically Based Pharmacokinetic Modelling Approach with Tocilizumab as a Case Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2418-5970","authenticated-orcid":false,"given":"Xian","family":"Pan","sequence":"first","affiliation":[{"name":"Certara Predictive Technologies Division, Certara UK Limited, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division, Certara UK Limited, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4223-6754","authenticated-orcid":false,"given":"Felix","family":"Stader","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division, Certara UK Limited, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1841-9646","authenticated-orcid":false,"given":"Abdallah","family":"Derbalah","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division, Certara UK Limited, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masoud","family":"Jamei","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division, Certara UK Limited, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Gardner","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division, Certara UK Limited, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"ref_1","unstructured":"(2023, June 06). U.S. Food & Drug Administration, Drug-Drug Interaction Assessment for Therapeutic Proteins, Guidance for Industry, Available online: www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/drug-drug-interaction-assessment-therapeutic-proteins-guidance-industry."},{"key":"ref_2","unstructured":"(2024, June 10). ICH Guideline M12 on Drug Interaction Studies. Available online: https:\/\/database.ich.org\/sites\/default\/files\/ICH_M12_Step4_Guideline_2024_0521_0.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1124\/dmd.107.018747","article-title":"Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer","volume":"36","author":"Morgan","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/clpt.2014.143","article-title":"Cancer, inflammation, and therapy: Effects on cytochrome p450-mediated drug metabolism and implications for novel immunotherapeutic agents","volume":"96","author":"Harvey","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1124\/dmd.122.000926","article-title":"Physiologically Based Pharmacokinetic Modeling To Predict Drug-Biologic Interactions with Cytokine Modulators: Are These Relevant and Is Interleukin-6 Enough?","volume":"50","author":"Chen","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1002\/jcph.1093","article-title":"Disease-Drug Interactions in Inflammatory States via Effects on CYP-Mediated Drug Clearance","volume":"58","author":"Coutant","year":"2018","journal-title":"J. Clin. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.7150\/ijbs.4989","article-title":"IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-inflammatory activities of IL-6","volume":"8","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/clpt.2013.79","article-title":"A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: Suppression of CYP3A by IL-6","volume":"94","author":"Machavaram","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.intimp.2005.05.010","article-title":"Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family","volume":"5","author":"Mihara","year":"2005","journal-title":"Int. Immunopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1182\/blood-2008-05-155846","article-title":"Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease","volume":"112","author":"Nishimoto","year":"2008","journal-title":"Blood"},{"key":"ref_11","first-page":"1426","article-title":"Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I\/II clinical study","volume":"30","author":"Nishimoto","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/clpt.2011.35","article-title":"Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis","volume":"89","author":"Schmitt","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1111\/cts.13164","article-title":"Utilization of physiologically-based pharmacokinetic model to assess disease-mediated therapeutic protein-disease-drug interaction in immune-mediated inflammatory diseases","volume":"15","author":"Wang","year":"2022","journal-title":"Clin. Transl. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1208\/s12248-016-9890-5","article-title":"Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein-Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6","volume":"18","author":"Jiang","year":"2016","journal-title":"AAPS J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1208\/s12248-015-9819-4","article-title":"A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins","volume":"18","author":"Gill","year":"2016","journal-title":"AAPS J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s40262-013-0097-y","article-title":"A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: Prediction of drug-drug interaction between rosuvastatin and cyclosporine","volume":"53","author":"Jamei","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.1993.73.1.1","article-title":"Interstitial-lymphatic mechanisms in the control of extracellular fluid volume","volume":"73","author":"Aukland","year":"1993","journal-title":"Physiol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/j.1748-1716.1987.tb08257.x","article-title":"Fluid and protein fluxes across small and large pores in the microvasculature. Application of two-pore equations","volume":"131","author":"Rippe","year":"1987","journal-title":"Acta Physiol. Scand."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1208\/s12248-014-9640-5","article-title":"Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model","volume":"16","author":"Li","year":"2014","journal-title":"AAPS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1007\/s11095-005-6650-0","article-title":"Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition","volume":"22","author":"Mager","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1080\/1744666X.2022.2060204","article-title":"Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: A randomized, double-blind trial","volume":"18","author":"Schwabe","year":"2022","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_23","unstructured":"(2025, March 24). ACTEMRA\u00ae (Tocilizumab) Injection, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/125276s144,125472s056lbl.pdf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1083\/jcb.83.1.82","article-title":"Rapid stimulation of pinocytosis in human carcinoma cells A-431 by epidermal growth factor","volume":"83","author":"Haigler","year":"1979","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1080\/19420862.2019.1605270","article-title":"An in vitro FcRn- dependent transcytosis assay as a screening tool for predictive assessment of nonspecific clearance of antibody therapeutics in humans","volume":"11","author":"Chung","year":"2019","journal-title":"MAbs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1177\/0091270009350623","article-title":"Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis","volume":"50","author":"Frey","year":"2010","journal-title":"J. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/jcph.1795","article-title":"Differential Binding of Sarilumab and Tocilizumab to IL-6Ralpha and Effects of Receptor Occupancy on Clinical Parameters","volume":"61","author":"Xu","year":"2021","journal-title":"J. Clin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1210\/jc.2002-021687","article-title":"Interleukin-6 stimulates lipolysis and fat oxidation in humans","volume":"88","author":"Steensberg","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alfinito, E., Beccaria, M., and Ciccarese, M. (2020). Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors. Biosensors, 10.","DOI":"10.20944\/preprints202007.0378.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1432-1033.1994.tb18991.x","article-title":"Biosynthesis and half-life of the interleukin-6 receptor and its signal transducer gp130","volume":"223","author":"Gerhartz","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1124\/dmd.111.038679","article-title":"Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture","volume":"39","author":"Dickmann","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1002\/cpt.3560","article-title":"Cytokine Dynamics in Action: A Mechanistic Approach to Assess Interleukin 6 Related Therapeutic Protein-Drug-Disease Interactions","volume":"117","author":"Pan","year":"2025","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12964-019-0356-0","article-title":"Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor alpha to gp130 expression: Fusing experimental insights and dynamic modelling","volume":"17","author":"Reeh","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14116","DOI":"10.1016\/S0021-9258(19)85216-X","article-title":"Evidence for an acute phase response in human intestinal epithelial cells","volume":"268","author":"Molmenti","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1208\/s12248-019-0309-y","article-title":"Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations","volume":"21","author":"Machavaram","year":"2019","journal-title":"AAPS J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s40262-019-00827-4","article-title":"Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population","volume":"59","author":"Abduljalil","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/psp4.12794","article-title":"Prediction of CYP-mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator","volume":"11","author":"Kilford","year":"2022","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/cpt.1955","article-title":"Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling","volume":"108","author":"Zhang","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1002\/cpt.3491","article-title":"The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study","volume":"117","author":"Terrier","year":"2025","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/jcph.826","article-title":"Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA","volume":"57","author":"Abdallah","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"620","DOI":"10.5414\/CP201904","article-title":"Pharmacokinetics and pharmacodynamics of tocilizumab after subcutaneous administration in patients with rheumatoid arthritis","volume":"51","author":"Zhang","year":"2013","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ferreira, R.C., Freitag, D.F., Cutler, A.J., Howson, J.M., Rainbow, D.B., Smyth, D.J., Kaptoge, S., Clarke, P., Boreham, C., and Coulson, R.M. (2013). Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003444"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100358","DOI":"10.1016\/j.mcpsp.2022.100358","article-title":"Acute cyclosporine overdose: A systematic review","volume":"6","author":"Ershad","year":"2023","journal-title":"Med. Cl\u00ednica Pr\u00e1ctica"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lieberman, P., and Anderson, J.A. (2007). Theophylline. Allergic Diseases: Diagnosis and Treatment, Humana Press.","DOI":"10.1007\/978-1-59745-382-0"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1136\/ard.2008.092932","article-title":"IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: Results from a 24-week multicentre randomised placebo-controlled trial","volume":"67","author":"Emery","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1749-6632.1989.tb24016.x","article-title":"IL-6 is the principal factor produced by synovia of patients with rheumatoid arthritis that induces B-lymphocytes to secrete immunoglobulins","volume":"557","author":"Nawata","year":"1989","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1136\/ard.53.8.521","article-title":"Circadian rhythm of serum interleukin-6 in rheumatoid arthritis","volume":"53","author":"Arvidson","year":"1994","journal-title":"Ann. Rheum. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/0049-0172(92)90046-G","article-title":"Cyclosporine in rheumatoid arthritis","volume":"22","author":"Dijkmans","year":"1992","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2165\/11319980-000000000-00000","article-title":"CYP-mediated therapeutic protein-drug interactions: Clinical findings, proposed mechanisms and regulatory implications","volume":"49","author":"Lee","year":"2010","journal-title":"Clin. Pharmacokinet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1124\/dmd.113.052225","article-title":"Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: A white paper","volume":"41","author":"Evers","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1080\/17425255.2016.1211109","article-title":"Therapeutic protein-drug interactions: Plausible mechanisms and assessment strategies","volume":"12","author":"Zhou","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"31185","DOI":"10.1074\/jbc.M110.107805","article-title":"Regulation of MRP2\/ABCC2 and BSEP\/ABCB11 expression in sandwich cultured human and rat hepatocytes exposed to inflammatory cytokines TNF-alpha, IL-6, and IL-1beta","volume":"285","author":"Diao","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1124\/dmd.114.061317","article-title":"Establishment of a hepatocyte-kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters","volume":"43","author":"Nguyen","year":"2015","journal-title":"Drug Metab. Dispos."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/7\/896\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:07:41Z","timestamp":1760033261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/7\/896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,10]]},"references-count":53,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["pharmaceutics17070896"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17070896","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,10]]}}}