{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:29:04Z","timestamp":1768318144335,"version":"3.49.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Systemic pharmacokinetic (PK) studies can reflect the overall exposure of orally inhaled drug Products (OIDPs) in the blood after inhalation into the lung and can be used to evaluate the bioequivalence of test and reference products. The aim of this article is: (1) to study the PK characteristics and bioequivalence of ipratropium bromide (IB) inhalation aerosol, reference and test products in healthy Chinese subjects; (2) to establish a physiologically based pharmacokinetic (PBPK) model and verify the accuracy of the model in predicting bioequivalence; (3) attempt to use the model to predict the regional distribution of particles in the lung after inhalation, and discuss the effect of gastrointestinal drug absorption of IB on systemic exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study involved two clinical studies. Clinical study-1 (registration number: CTR20201284) was used with non-clinical data to construct and validate a PBPK model in the B<jats:sup>2<\/jats:sup>O simulator, a web-based virtual drug development platform. This model assessed different test and reference products\u2019 bioequivalence. Results were compared to a second clinical study (Clinical study-2: registration number CTR20202291). The particles\u2019 regional distribution in the lung and the gastrointestinal absorption effect on systemic exposure were discussed based on the simulation results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The established PBPK model successfully simulated the <jats:italic>in vivo<\/jats:italic> PK characteristics of IB inhalation aerosol, with <jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup> close to 1. Gastrointestinal absorption had a negligible effect on systemic exposure. Particles accumulated in the alveolar area were cleared within an hour, followed by particles in the bronchioles and bronchi.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This model provided a reliable method for exploring the correlation between <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> PK studies of IB inhalation aerosols. According to the simulation results, the test and reference products were bioequivalent.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2023.1056318","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T08:35:08Z","timestamp":1675758908000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Bioequivalence study of ipratropium bromide inhalation aerosol using PBPK modelling"],"prefix":"10.3389","volume":"10","author":[{"given":"Jisheng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keheng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuguang","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,7]]},"reference":[{"key":"ref1","volume-title":"Global strategy for asthma management and prevention","year":"2021"},{"key":"ref2","volume-title":"Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease","year":"2022"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/S0140-6736(19)31147-X","article-title":"Prevalence, risk factors, and management of asthma in China: a national cross-sectional study","volume":"394","author":"Huang","year":"2019","journal-title":"Lancet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1016\/S0140-6736(18)30841-9","article-title":"Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China pulmonary health [CPH] study): a national cross-sectional study","volume":"391","author":"Wang","year":"2018","journal-title":"Lancet"},{"key":"ref5","year":""},{"key":"ref6","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0099-5428(03)30006-1","article-title":"Ipratropium bromide: drug metabolism and pharmacokinetics","volume":"30","author":"H Abdine F Belal","year":"2003","journal-title":"Profiles Drug Subst Excip Relat Methodol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"215","DOI":"10.2165\/00151829-200504030-00006","article-title":"Ipratropium bromide HFA","volume":"4","author":"K","year":"2005","journal-title":"Treat Respir Med."},{"key":"ref8","volume-title":"Guidelines for bioequivalence studies of generic drugs for oral inhalation preparations","year":""},{"key":"ref9","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1208\/s12248-015-9733-9","article-title":"International guidelines for bioequivalence of locally acting orally inhaled drug products: similarities and differences","volume":"17","author":"Lu","year":"2015","journal-title":"AAPS J."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1208\/s12248-015-9736-6","article-title":"Pharmacokinetics of orally inhaled drug products","volume":"17","author":"Hochhaus","year":"2015","journal-title":"AAPS J."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1021\/acs.molpharmaceut.2c00112","article-title":"iBCS: 2. 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