{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:04:58Z","timestamp":1784693098215,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>Hydroxyurea is a cornerstone therapy for sickle cell anemia; however, evidence guiding its use during lactation remains limited. This study aimed to develop a population pharmacokinetic (PK) model to characterize hydroxyurea disposition in maternal plasma and breast milk, and to quantify infant exposure under clinically relevant breastfeeding scenarios. Population PK modeling was conducted using data from the HELPS study (NCT02990598) with nonlinear mixed\u2010effects modeling. Maternal plasma PK parameters were first estimated using observed plasma concentration data, followed by estimation of parameters characterizing drug transfer into breast milk. Model\u2010based stochastic simulations were performed across infant ages 0\u20139\u2009months to evaluate exposure, expressed as the World Health Organization (WHO)\u2010recommended relative infant dose (RID), with 10% as the consensus safety threshold. The model diagnostics demonstrated that both plasma and breast milk PK were adequately described by the model. Simulation analyses demonstrated that the estimated RID remained below 10% across all evaluated infant age groups. This integrated plasma\u2010breast milk population PK model provides a quantitative framework to assess lactational drug exposure. The findings suggest that infant exposure to hydroxyurea through breastfeeding is unlikely to exceed the 10% safety threshold across all age groups (0\u20139\u2009months), supporting continued maternal therapy during lactation with appropriate clinical oversight.<\/jats:p>","DOI":"10.1002\/cpt.70394","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:40:18Z","timestamp":1784691618000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Model\u2010Informed Evaluation of Hydroxyurea Exposure During Lactation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0350-1965","authenticated-orcid":false,"given":"Anhar","family":"Hosawi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Physiology, &amp; Neurobiology University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-1208","authenticated-orcid":false,"given":"Kei","family":"Irie","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Dong","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Ware","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Center for Breastfeeding Medicine and Division of General Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Ware","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-9826","authenticated-orcid":false,"given":"Tomoyuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/phar.2793","article-title":"Hydroxyurea treatment for sickle cell anemia during pregnancy and lactation: current evidence and knowledge gaps","volume":"43","author":"Dong M.","year":"2023","journal-title":"Pharmacotherapy"},{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1517\/14740338.2015.1088827","article-title":"Hydroxyurea therapy for sickle cell anemia","volume":"14","author":"McGann P.T.","year":"2015","journal-title":"Expert Opin. 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Pharmacol."},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1038\/515S2a","article-title":"Epidemiology: a moving target","volume":"515","author":"Pleasants S.","year":"2014","journal-title":"Nature"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.bjhh.2014.05.007","article-title":"Clinical complications in pregnant women with sickle cell disease: prospective study of factors predicting maternal death or near miss","volume":"36","author":"Resende Cardoso P.S.","year":"2014","journal-title":"Rev. Bras. Hematol. Hemoter."},{"key":"e_1_2_11_7_1","first-page":"368","article-title":"Breastfeeding: common questions and answers","volume":"98","author":"Westerfield K.L.","year":"2018","journal-title":"Am. Fam. 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