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The final physiologically\u2010based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration\u2010time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6\u201330\u2009mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150\u2009\u03bcg\/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg\u2010p ontogenies), and pregnancy, especially if nonstandard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle\u2010mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the body mass index of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administration. Administering lower doses over a longer period may attenuate the dependence on bile micelle\u2010mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administration of ivermectin by complex generics in development.<\/jats:p>","DOI":"10.1002\/psp4.12950","type":"journal-article","created":{"date-parts":[[2023,2,25]],"date-time":"2023-02-25T07:38:26Z","timestamp":1677310706000},"page":"598-609","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PBPK modeling of ivermectin\u2014Considerations for the purpose of developing alternative routes to optimize its safety profile"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-0081","authenticated-orcid":false,"given":"Karen","family":"Rowland\u00a0Yeo","sequence":"first","affiliation":[{"name":"Certara UK Limited (Simcyp Division)  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wesche","sequence":"additional","affiliation":[{"name":"Certara Inc  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920112800399248"},{"key":"e_1_2_8_3_1","first-page":"175","article-title":"The embryogenesis of Onchocerca volvulus over the first year after a single dose of ivermectin","volume":"42","author":"Duke B","year":"1991","journal-title":"Trop Med Parasitol"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127002401382731"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050131"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006020"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz083"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30163-4"},{"key":"e_1_2_8_9_1","unstructured":"WHO.WHO preferred product characteristics: endectocide for malaria transmission control.2016http:\/\/www. who.int\/malaria\/publications\/atoz\/endectocide\u2010transmissioncontrol\/en\/. 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