{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:26:57Z","timestamp":1790000817999,"version":"4.0.1"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"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":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Physiologically based pharmacokinetic (PBPK) modeling of placental drug transfer is an evolving tool for predicting fetal drug exposure. In this study, a pregnancy\u2010specific metformin PBPK model was developed,\u00a0and the following four approaches were evaluated to predict metformin placental transfer: (1) perfusion\u2010limited model, and permeability\u2010limited models using (2) ex\u00a0vivo cotyledon open system apparent clearance, (3) ex\u00a0vivo cotyledon closed system data fit to a three\u2010compartment model to estimate clearance, and (4) active transport kinetics and passive clearance. Simulated metformin maternal plasma concentrations (MPCs) and umbilical cord venous plasma concentrations (UCCs) were compared to observed in\u00a0vivo data from subjects with gestational diabetes mellitus taking metformin 500\u2009mg twice daily. Model selection criteria were determined by the percentage of observed clinical data falling within the 5th to 95th percentiles of the simulated population. Among the approaches, the model that included passive permeability and in\u00a0vitro intrinsic transporter clearances (Approach 4) best described placental metformin transfer, with 92% of UCCs falling within the 5th to 95th percentiles of the simulated population. Furthermore, maternal uptake transport had the largest influence on predicted UCCs. A two\u2010fold increase in maternal uptake transport increased the predicted population mean UCC\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    by 97%, whereas a 0.5\u2010fold decrease resulted in a 49% decrease in UCC\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    . This refined PBPK model offers a valuable framework for predicting placental transfer and fetal exposure of metformin when placental transporters are altered throughout pregnancy and\/or with pathological conditions.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70136","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T19:40:33Z","timestamp":1764099633000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparison of Metformin\n                    <scp>PBPK<\/scp>\n                    Models Incorporating Placental Transfer to Predict Fetal and Maternal Exposure"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9977-1184","authenticated-orcid":false,"given":"Jacqueline B.","family":"Tiley","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-0168","authenticated-orcid":false,"given":"Mattie E.","family":"Hartauer","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0622-1034","authenticated-orcid":false,"given":"Tajhia L.","family":"Whigham","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-4350","authenticated-orcid":false,"given":"Ma\u00eflys De Sousa","family":"Mendes","sequence":"additional","affiliation":[{"name":"Simcyp Division Certara UK Limited  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-4929","authenticated-orcid":false,"given":"Kim L. R.","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2530-8189","authenticated-orcid":false,"given":"Mary F.","family":"Hebert","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Washington  Seattle Washington USA"},{"name":"Department of Obstetrics and Gynecology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"1","article-title":"Trends and Characteristics in Gestational Diabetes: United States, 2016\u20102020","volume":"71","author":"Gregory E. 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