{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:43:08Z","timestamp":1790970188145,"version":"4.1.0"},"reference-count":69,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds\u2019 pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs\u2019 PK in both the pregnant woman and the fetus. The PBPKPlus\u2122 module in GastroPlus\u00ae was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for metabolically cleared compounds.<\/jats:p>","DOI":"10.3390\/pharmaceutics16010096","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T06:52:14Z","timestamp":1704955934000},"page":"96","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2629-8039","authenticated-orcid":false,"given":"Maxime","family":"Le Merdy","sequence":"first","affiliation":[{"name":"Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke Xu","family":"Szeto","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Perrier","sequence":"additional","affiliation":[{"name":"PhinC Development, 36 Rue Victor Basch, 91300 Massy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Bolger","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viera","family":"Lukacova","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"ref_1","unstructured":"U.S. Food and Drug Administration (2023, December 12). Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials Guidance for Industry, Available online: https:\/\/www.fda.gov\/media\/112195\/download."},{"key":"ref_2","unstructured":"European Medicines Agency (2023, December 12). Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-risk-assessment-medicinal-products-human-reproduction-lactation-data-labelling_en.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/cpt.2843","article-title":"A Comparison of FDA and EMA Pregnancy and Lactation Labeling","volume":"113","author":"Kappel","year":"2023","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1542\/peds.113.S3.984","article-title":"Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents)","volume":"113","author":"Brent","year":"2004","journal-title":"Pediatrics"},{"key":"ref_5","unstructured":"European Medicines Agency (2023, December 12). Guideline on the Exposure to Medicinal Products during Pregnancy: Need for Post-Authorisation Data. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/regulatory-procedural-guideline\/guideline-exposure-medicinal-products-during-pregnancy-need-post-authorisation-data_en.pdf."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Berezowska, M., Sharma, P., Pilla Reddy, V., and Coppola, P. (2023). Physiologically Based Pharmacokinetic modelling of drugs in pregnancy: A mini-review on availability and limitations. Fundam. Clin. Pharmacol., e12967.","DOI":"10.1111\/fcp.12967"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"687978","DOI":"10.3389\/fped.2021.687978","article-title":"Physiologically Based Pharmacokinetics Model in Pregnancy: A Regulatory Perspective on Model Evaluation","volume":"9","author":"Coppola","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1208\/s12248-021-00603-y","article-title":"PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus","volume":"23","author":"Szeto","year":"2021","journal-title":"AAPS J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2016.08.001","article-title":"Drug Metabolism in the Liver","volume":"21","author":"Almazroo","year":"2017","journal-title":"Clin. Liver Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1080\/10837450902891295","article-title":"Drug metabolism and pharmacokinetics","volume":"41","author":"Benedetti","year":"2009","journal-title":"Drug Metab. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.2174\/1389450118666170125144557","article-title":"Cytochrome P450 Structure, Function and Clinical Significance: A Review","volume":"19","author":"Manikandan","year":"2018","journal-title":"Curr. Drug Targets"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"365","DOI":"10.2165\/11597440-000000000-00000","article-title":"Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: A database for parameters required in physiologically based pharmacokinetic modelling","volume":"51","author":"Abduljalil","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s40262-017-0594-5","article-title":"A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways","volume":"57","author":"Dallmann","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gong, C., Bertagnolli, L.N., Boulton, D.W., and Coppola, P. (2023). A Literature Review of Changes in Phase II Drug-Metabolizing Enzyme and Drug Transporter Expression during Pregnancy. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15112624"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s40262-016-0457-5","article-title":"A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways","volume":"56","author":"Lui","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_16","unstructured":"Simulations Plus (2023). GastroPlus Manual, Simulations Plus."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"931","DOI":"10.2165\/00003088-200645090-00005","article-title":"Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children","volume":"45","author":"Johnson","year":"2006","journal-title":"Clin. Pharmacokinet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1023\/A:1018989211864","article-title":"Comparison of CYP2D6 content and metoprolol oxidation between microsomes isolated from human livers and small intestines","volume":"16","author":"Madani","year":"1999","journal-title":"Pharm. Res."},{"key":"ref_19","unstructured":"Lukacova, V., Parrott, N.J., Fraczkiewicz, G., Bolger, M.B., and Woltosz, W.S. (2008, January 16\u201320). General approach to calculation of tissue:plasma partition coefficients for physiologically based pharmacokinetic (PBPK) modeling. Proceedings of the AAPS Annual Meeting, Atlanta, GA, USA."},{"key":"ref_20","first-page":"1552","article-title":"Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism","volume":"283","author":"Paine","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1007\/s11095-011-0446-1","article-title":"Fatty acid binding proteins: Potential chaperones of cytosolic drug transport in the enterocyte?","volume":"28","author":"Trevaskis","year":"2011","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1124\/dmd.113.052548","article-title":"The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst","volume":"41","author":"Pearce","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1080\/00498250310001646353","article-title":"Predicting drug clearance from recombinantly expressed CYPs: Intersystem extrapolation factors","volume":"34","author":"Proctor","year":"2004","journal-title":"Xenobiotica"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1128\/AAC.23.5.721","article-title":"Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route","volume":"23","author":"Mattila","year":"1983","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/BF00607962","article-title":"Influence of dose and route of administration on disposition of metronidazole and its major metabolites","volume":"30","author":"Loft","year":"1986","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_26","first-page":"373","article-title":"The isolation and identification of the urinary oxidative metabolites of metronidazole in man","volume":"161","author":"Stambaugh","year":"1968","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/clpt.2013.96","article-title":"Meta-Analysis of cyp2d6 Metabolizer Phenotype and Metoprolol Pharmacokinetics","volume":"94","author":"Blake","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_28","unstructured":"U.S. Food and Drug Administration (2023, December 12). LOPRESSOR (Metoprolol Tartrate) Tablet FDA Label, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2008\/017963s062,018704s021lbl.pdf."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.clpt.2004.07.002","article-title":"Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics","volume":"76","author":"Kirchheiner","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113S","DOI":"10.1111\/j.1365-2125.1985.tb02751.x","article-title":"Investigation of drug absorption from the gastrointestinal tract of man","volume":"19","author":"Godbillon","year":"1985","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/clpt.1985.114","article-title":"Pregnancy-induced increase in metoprolol metabolism","volume":"37","author":"Lindberg","year":"1985","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_32","unstructured":"U.S. Food and Drug Administration (2023, December 12). MIdazolam Injectable Pharmacology and Toxicology Review, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/pre96\/018654Orig1s000rev.pdf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/0009-9236(95)90068-3","article-title":"Interaction between grapefruit juice and midazolam in humans","volume":"58","author":"Kupferschmidt","year":"1995","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/BF00547375","article-title":"Dose dependent pharmacokinetics of midazolam","volume":"29","author":"Bornemann","year":"1985","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/clpt.2008.1","article-title":"Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: A University of Washington specialized center of research study","volume":"84","author":"Hebert","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1080\/00498250600683262","article-title":"Prediction of in vivo drug clearance from in vitro data. II: Potential inter-ethnic differences","volume":"36","author":"Inoue","year":"2006","journal-title":"Xenobiotica"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/clpt.1983.107","article-title":"Placental transfer and maternal midazolam kinetics","volume":"33","author":"Kanto","year":"1983","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1365-2125.1979.tb04715.x","article-title":"Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose","volume":"8","author":"Houghton","year":"1979","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1046\/j.0306-5251.2001.01500.x","article-title":"Polymorphisms of CYP2A6 and its practical consequences","volume":"52","author":"Raunio","year":"2001","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_40","first-page":"174","article-title":"Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction","volume":"16","year":"2017","journal-title":"EXCLI J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1159\/000237958","article-title":"Pharmacokinetics of Metronidazole in pregnant women","volume":"27","author":"Amon","year":"1981","journal-title":"Chemotherapy"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3109\/14767058.2010.497573","article-title":"Pharmacokinetics of metronidazole in pregnant patients with bacterial vaginosis","volume":"24","author":"Wang","year":"2011","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1093\/jac\/13.3.279","article-title":"The pharmacokinetics of a single intravenous dose of metronidazole in pregnant patients","volume":"13","author":"Visser","year":"1984","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/j.1365-2125.1984.tb02465.x","article-title":"Placental transfer of metronidazole and tinidazole in early human pregnancy after a single infusion","volume":"18","author":"Karhunen","year":"1984","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_45","first-page":"43","article-title":"Placental transfer of metronidazole in the first trimester of pregnancy","volume":"12","author":"Heisterberg","year":"1984","journal-title":"J. Perinat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S692","DOI":"10.1016\/j.ajog.2021.11.1142","article-title":"Development of physiologically based pharmacokinetic model using artificial intelligence based approaches for pravastatin during pregnancy","volume":"226","author":"Kammala","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1021\/acs.molpharmaceut.8b01276","article-title":"Physiologically Based Pharmacokinetic\/Pharmacodynamic Model for Caffeine Disposition in Pregnancy","volume":"16","author":"Darakjian","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1002\/psp4.12899","article-title":"Minimal physiologically-based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids","volume":"12","author":"Krzyzanski","year":"2023","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"793346","DOI":"10.3389\/fphar.2021.793346","article-title":"Physiologically Based Pharmacokinetic Modeling in Pregnant Women Suggests Minor Decrease in Maternal Exposure to Olanzapine","volume":"12","author":"Zheng","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1097\/FTD.0000000000000724","article-title":"Pregnancy Alters CYP- and UGT-Mediated Metabolism of Buprenorphine","volume":"42","author":"Zhang","year":"2020","journal-title":"Ther. Drug Monit."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.eplepsyres.2018.01.011","article-title":"UGT polymorphisms and lamotrigine clearance during pregnancy","volume":"140","author":"Petrenaite","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1007\/s40262-017-0539-z","article-title":"Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy","volume":"56","author":"Dallmann","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_53","unstructured":"Rasmussen, K.M., and Yaktine, A.L. (2020, July 28). Committee to Reexamine IOM Pregnancy Weight Guidelines, Weight Gain During Pregnancy: Reexamining the Guidelines, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK32813\/."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1124\/dmd.120.000067","article-title":"Gestational Age-Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics","volume":"48","author":"Anoshchenko","year":"2020","journal-title":"Drug Metab. Dispos."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.2105\/AJPH.87.12.1984","article-title":"The pattern of maternal weight gain in women with good pregnancy outcomes","volume":"87","author":"Carmichael","year":"1997","journal-title":"Am. J. Public Health"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1007\/s40262-017-0618-1","article-title":"Fetal Physiologically-Based Pharmacokinetic Models: Systems Information on Fetal Biometry and Gross Composition","volume":"57","author":"Abduljalil","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1124\/dmd.117.075192","article-title":"Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses","volume":"45","author":"Zhang","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1124\/dmd.116.073957","article-title":"Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model II: Verification of the model for passive placental permeability drugs","volume":"45","author":"Zhang","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1002\/cpt.1748","article-title":"Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling","volume":"107","author":"Freriksen","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s40262-020-00861-7","article-title":"Integration of Placental Transfer in a Fetal-Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus","volume":"59","author":"Mian","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"114640","DOI":"10.1016\/j.taap.2019.114640","article-title":"Prediction of maternal and foetal exposures to perfluoroalkyl compounds in a Spanish birth cohort using toxicokinetic modelling","volume":"379","author":"Brochot","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"105068","DOI":"10.1016\/j.ejps.2019.105068","article-title":"Using mechanistic physiologically-based pharmacokinetic models to assess prenatal drug exposure: Thalidomide versus efavirenz as case studies","volume":"140","author":"Atoyebi","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1124\/dmd.121.000538","article-title":"Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation","volume":"49","author":"Anoshchenko","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"106349","DOI":"10.1016\/j.ejps.2022.106349","article-title":"Application of PBPK modeling in predicting maternal and fetal pharmacokinetics of levetiracetam during pregnancy","volume":"181","author":"Chen","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"100111","DOI":"10.1016\/j.comtox.2019.100111","article-title":"Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data","volume":"12","author":"Codaccioni","year":"2019","journal-title":"Comput. Toxicol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1111\/j.1365-2125.2012.04363.x","article-title":"A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4","volume":"74","author":"Gaohua","year":"2012","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1111\/bcp.12207","article-title":"Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19","volume":"77","author":"Ke","year":"2014","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"S70","DOI":"10.1002\/jcph.1491","article-title":"van den Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal-Fetal Drug Transfer","volume":"59","author":"Dallmann","year":"2019","journal-title":"J. Clin. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Yamashita, M., and Markert, U.R. (2021). Overview of Drug Transporters in Human Placenta. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313149"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/1\/96\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:44:02Z","timestamp":1760103842000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/1\/96"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,10]]},"references-count":69,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["pharmaceutics16010096"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16010096","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,10]]}}}