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Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal\u2010placental\u2010fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco\u20102 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2\u2010fold criteria. The PBPK model predicted a mean cord\u2010to\u2010maternal plasma ratio of 0.98 (range, 0.86\u20101.06) at term, which agrees with experimental observations of 0.78 (range, 0.59\u20100.93). Predicted nifedipine exposure was 1.4\u2010, 2.0\u2010, and 3.0\u2010fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy.<\/jats:p>","DOI":"10.1002\/jcph.2404","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T09:44:51Z","timestamp":1706867091000},"page":"568-577","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mechanistic Framework to Predict Maternal\u2010Placental\u2010Fetal Pharmacokinetics of Nifedipine Employing Physiologically Based Pharmacokinetic Modeling Approach"],"prefix":"10.1002","volume":"64","author":[{"given":"Marya Ant\u00f4nya","family":"Werdan Rom\u00e3o","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Farmacometria (LabFarma) Faculdade de Farm\u00e1cia Universidade Federal do Rio de Janeiro  Rio de Janeiro RJ Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Pinto","sequence":"additional","affiliation":[{"name":"Universidade Federal de Ouro Preto  Ouro Preto MG Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Carvalho","family":"Cavalli","sequence":"additional","affiliation":[{"name":"Departamento de Obstetr\u00edcia e Ginecologia Faculdade de Medicina de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo  Ribeir\u00e3o Preto SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldo","family":"Duarte","sequence":"additional","affiliation":[{"name":"Departamento de Obstetr\u00edcia e Ginecologia Faculdade de Medicina de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo  Ribeir\u00e3o Preto SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-058X","authenticated-orcid":false,"given":"Nat\u00e1lia Valadares","family":"de Moraes","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-9237","authenticated-orcid":false,"given":"Khaled","family":"Abduljalil","sequence":"additional","affiliation":[{"name":"Simcyp Division Certara UK Limited  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7699-2665","authenticated-orcid":false,"given":"Fernanda de Lima","family":"Moreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacometria (LabFarma) Faculdade de Farm\u00e1cia Universidade Federal do Rio de Janeiro  Rio de Janeiro RJ Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199604001-01494"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/10641955.2022.2056196"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.122.19751"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000004436"},{"key":"e_1_2_10_6_1","unstructured":"Adalat\u00aeCC.FDA Drug Sheet. 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