{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:11:49Z","timestamp":1787314309760,"version":"build-2736575974"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T00:00:00Z","timestamp":1720396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    As detailed information on the pharmacokinetics (PK) of labetalol in pregnant people are lacking, the aims of this study were: (1) to build a physiologically based PK (PBPK) model of labetalol in non\u2010pregnant individuals that incorporates different CYP2C19 genotypes (specifically, *1\/*1, *1\/*2 or *3, *2\/*2, and *17\/*17); (2) to translate this model to the second and third trimester of pregnancy; and (3) to combine the model with a previously published direct pharmacodynamic (PD) model to predict the blood pressure lowering effect of labetalol in the third trimester. Clinical data for model evaluation was obtained from the scientific literature. In non\u2010pregnant populations, the mean ratios of simulated versus observed peak concentration (C\n                    <jats:sub>max<\/jats:sub>\n                    ), time to reach C\n                    <jats:sub>max<\/jats:sub>\n                    (T\n                    <jats:sub>max<\/jats:sub>\n                    ), and exposure (area under the plasma concentration\u2013time curve, AUC) were 0.94, 0.82, and 1.16, respectively. The pregnancy PBPK model captured the observed PK adequately, but clearance was slightly underestimated with mean ratios of simulated versus observed C\n                    <jats:sub>max<\/jats:sub>\n                    , T\n                    <jats:sub>max<\/jats:sub>\n                    , and AUC of 1.28, 1.30, and 1.39, respectively. The results suggested that pregnant people with CYP2C19 *2\/*2 alleles have similar labetalol exposure and trough levels compared to non\u2010pregnant controls, whereas those with other alleles were found to have increased exposure and trough concentrations. Importantly, the pregnancy PBPK\/PD model predicted that, despite increased exposure in some genotypes, the blood pressure lowering effect was broadly comparable across all genotypes. In view of the large inter\u2010individual variability and the potentially increasing blood pressure during pregnancy, patients may need to be closely monitored for achieving optimal therapeutic effects and avoiding adverse events.\n                  <\/jats:p>","DOI":"10.1002\/jcph.2496","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T06:38:50Z","timestamp":1720420730000},"page":"1443-1455","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Labetalol Dosing in Pregnancy: PBPK\/PD and CYP2C19 Polymorphisms"],"prefix":"10.1002","volume":"64","author":[{"given":"Xiaomei I.","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology Children's National Hospital  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dionna J.","family":"Green","sequence":"additional","affiliation":[{"name":"Office of Pediatric Therapeutics US Food and Drug Administration  Silver Spring MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"van den Anker","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Children's National Hospital  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin","family":"Calderon","sequence":"additional","affiliation":[{"name":"Division of Maternal\u2010Fetal Medicine Department of OB\/Gyn George Washington University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Homa","family":"Ahmadzia","sequence":"additional","affiliation":[{"name":"Division of Maternal\u2010Fetal Medicine Department of OB\/Gyn George Washington University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2005-9301","authenticated-orcid":false,"given":"Gilbert J.","family":"Burckart","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology US Food and Drug Administration  Silver Spring MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-5719","authenticated-orcid":false,"given":"Andr\u00e9","family":"Dallmann","sequence":"additional","affiliation":[{"name":"Bayer HealthCare SAS Loos, France on behalf of: Pharmacometrics\/Modeling &amp; Simulation Research &amp; Development Pharmaceuticals  Bayer AG Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2003.223"},{"key":"e_1_2_13_3_1","unstructured":"U.S.Food and Drug Administration: Pregnant women: scientific and ethical considerations for inclusion in clinical trials guidance for industry.2018. 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