{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T02:23:00Z","timestamp":1793499780876,"version":"4.5.0"},"reference-count":50,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV\u2010040110"],"award-info":[{"award-number":["INV\u2010040110"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Optimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically\u2010based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios and hence supplement clinical data to support dosing decisions. A PBPK model for the antiretroviral dolutegravir (mainly metabolized by UGT1A1) was verified using reported exposures in non\u2010pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates. The model was then applied to predict the impact of UGT1A1 phenotypes in extensive (EM), poor (PM), and ultra\u2010rapid metabolizers (UM). The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 PMs was 1.6\u2010fold higher than in EMs. The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 UMs mothers was 1.3\u2010fold lower than in EMs. The predicted mean systemic and umbilical vein concentrations were in excess of the dolutegravir IC\n                    <jats:sub>90<\/jats:sub>\n                    at 17, 28, and 40 gestational weeks, regardless of UGT1A1 phenotype, indicating that the standard dose of dolutegravir (50\u2009mg q.d., fed state) is generally appropriate in late pregnancy, across UGT1A1 phenotypes. Applying the model in breastfed infants, a 1.5\u2010, 1.7\u2010, and 2.2\u2010fold higher exposure in 2\u2010day\u2010old neonates, 10\u2010day\u2010old neonates, and infants who were UGT1A1 PMs, respectively, compared with EMs of the same age. However, it should be noted that the exposure in breastfed infants who were UGT1A1 PMs was still an order of magnitude lower than maternal exposure with a relative infant daily dose of &lt;2%, suggesting safe use of dolutegravir in breastfeeding women.\n                  <\/jats:p>","DOI":"10.1002\/psp4.13251","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T01:40:22Z","timestamp":1730338822000},"page":"1924-1938","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women"],"prefix":"10.1002","volume":"13","author":[{"given":"Jia","family":"Ning","sequence":"first","affiliation":[{"name":"Certara Predictive Technologies Division  Sheffield 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