{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:44:31Z","timestamp":1768265071755,"version":"3.49.0"},"reference-count":66,"publisher":"Wiley","issue":"S1","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Following the 2021 World Health Organization's updated recommendations on the management of HIV infection, millions of people living with HIV are currently switched from efavirenz\u2010based antiretroviral therapy to dolutegravir\u2010based antiretroviral therapy. Pregnant individuals transitioning from efavirenz to dolutegravir might be at increased risk of insufficient viral suppression in the immediate postswitch period because both efavirenz\u2010 and pregnancy\u2010related increases in hormone levels induce enzymes involved in dolutegravir metabolism, namely, cytochrome P450 3A4 and uridine 5\u2032\u2010diphospho\u2010glucuronosyltransferase 1A1. This study aimed at developing physiologically based pharmacokinetic models to simulate the switch from efavirenz to dolutegravir in the late second and third trimester. To this end, the drug\u2010drug interaction between efavirenz and the uridine 5\u2032\u2010diphospho\u2010glucuronosyltransferase 1A1 substrates dolutegravir and raltegravir was first simulated in nonpregnant subjects. After successful validation, the physiologically based pharmacokinetic models were translated to pregnancy and dolutegravir pharmacokinetics following efavirenz discontinuation were predicted. Modeling results indicated that, at the end of the second trimester, both efavirenz concentrations and dolutegravir trough concentrations fell below respective pharmacokinetic target thresholds (defined as reported thresholds producing 90%\u201095% of the maximum effect) during the time interval from 9.75 to 11\u00a0days after dolutegravir initiation. At the end of the third trimester, this time interval spanned from 10.3\u00a0days to &gt;4\u00a0weeks after dolutegravir initiation. These findings suggest that dolutegravir exposure in the immediate post\u2010efavirenz switch period during pregnancy may be suboptimal, leading to HIV viremia and, potentially, resistance. The clinical implications of these findings remain to be substantiated by future studies.<\/jats:p>","DOI":"10.1002\/jcph.2225","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T05:01:21Z","timestamp":1686805281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanistic Modeling of the Drug\u2010Drug Interaction Between Efavirenz and Dolutegravir: Is This Interaction Clinically Relevant When Switching From Efavirenz to Dolutegravir During Pregnancy?"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-5719","authenticated-orcid":false,"given":"Andr\u00e9","family":"Dallmann","sequence":"first","affiliation":[{"name":"Pharmacometrics\/Modeling &amp; Simulation Research &amp; Development Pharmaceuticals, Bayer AG  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"van den Anker","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Children's National Hospital  Washington District of Columbia USA"},{"name":"Paediatric Pharmacology and Pharmacometrics University Children's Hospital Basel University of Basel  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Homa K.","family":"Ahmadzia","sequence":"additional","affiliation":[{"name":"Division of Maternal\u2010Fetal Medicine Department of Obstetrics and Gynecology The George Washington University School of Medicine and Health Sciences  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natella","family":"Rakhmanina","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases Children's National Hospital  Washington District of Columbia USA"},{"name":"The George Washington University School of Medicine and Health Sciences  Washington District of Columbia USA"},{"name":"Elizabeth Glaser Pediatric AIDS Foundation  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"World Health Organization (WHO).Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2nd ed. Available at:https:\/\/www.who.int\/publications\/i\/item\/9789241549684. Accessed 21\/10\/2022."},{"key":"e_1_2_8_3_1","unstructured":"World Health Organization (WHO).Updated recommendations on first\u2010line and second\u2010line antiretroviral regimens and post\u2010exposure prophylaxis and recommendations on early infant diagnosis of HIV. Available at:https:\/\/www.who.int\/publications\/i\/item\/WHO\u2010CDS\u2010HIV\u201018.51. Accessed 21\/10\/2022."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1905230"},{"key":"e_1_2_8_5_1","first-page":"2021","article-title":"Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana","author":"Zash R","year":"2021","journal-title":"Abstract PEBLB14 IAS"},{"key":"e_1_2_8_6_1","first-page":"6","article-title":"Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana","author":"Zash R","year":"2020","journal-title":"AIDS"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0000000000002065"},{"key":"e_1_2_8_8_1","unstructured":"World Health Organization (WHO).Consolidated guidelines on HIV prevention testing treatment service delivery and monitoring: recommendations for a public health approach. Available at:https:\/\/www.who.int\/publications\/i\/item\/9789240031593. Accessed 21\/10\/2022."},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001845"},{"key":"e_1_2_8_10_1","volume-title":"Presented at: 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis therapy","author":"Wet J","year":"2016"},{"key":"e_1_2_8_11_1","volume-title":"Presented at: 18th International Workshop on Clinical Pharmacology of antiviral therapy","author":"Adkison K","year":"2017"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.7196\/SAMJ.2021.v112i3.16316"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa975"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2019.0122"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)32403-1"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.47102\/annals-acadmedsg.V41N12p559"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.curtheres.2014.05.002"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/hiv.12368"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.119.089052"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2045"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01543-07"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.107.016196"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00799-5"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498250701744633"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.655320"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00897-9"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12473"},{"key":"e_1_2_8_28_1","unstructured":"OSP Compound Library: Efavirenz. Available at:https:\/\/github.com\/Open\u2010Systems\u2010Pharmacology\/OSP\u2010PBPK\u2010Model\u2010Library\/tree\/v11.0.1\/Efavirenz. Accessed 09\/16\/2022."},{"key":"e_1_2_8_29_1","unstructured":"OSP Qualification Report: CYP3A4 DDI Qualification. Available at:https:\/\/github.com\/Open\u2010Systems\u2010Pharmacology\/OSP\u2010Qualification\u2010Reports\/tree\/v11.0\/DDI_Qualification_CYP3A4. Accessed 16\/09\/2022."},{"key":"e_1_2_8_30_1","unstructured":"OSP Compound Library: Raltegravir. Available at:https:\/\/github.com\/Open\u2010Systems\u2010Pharmacology\/OSP\u2010PBPK\u2010Model\u2010Library\/tree\/v11.0.1\/Raltegravir. Accessed 16\/09\/2022."},{"key":"e_1_2_8_31_1","unstructured":"OSP Qualification Report: UGT DDI Inhibition Qualification. Available at:https:\/\/github.com\/Open\u2010Systems\u2010Pharmacology\/OSP\u2010Qualification\u2010Reports\/tree\/v11.0\/DDI_Qualification_UGT. Accessed 16\/09\/2022."},{"key":"e_1_2_8_32_1","unstructured":"Dolutegravir PBPK Model. Available at:https:\/\/github.com\/Open\u2010Systems\u2010Pharmacology\/Pregnancy\u2010Models\/tree\/master\/Models\/Dolutegravir. Accessed 16\/09\/2022."},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.20058"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13020270"},{"key":"e_1_2_8_35_1","volume-title":"Effects of enzyme inducers, tipranavir and efavirenz, on the pharmacokinetics of the integrase inhibitor, dolutegravir (S\/GSK1349572). Presented at: 12th International Workshop on Clinical Pharmacology of HIV Therapy","author":"Song I","year":"2011"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.036103"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12300"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.43"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-017-0594-5"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12207"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e31823ff052"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP3283"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy161"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2020.07.008"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-6618(05)80029-5"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00842-09"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0093-2"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.12.2893"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq434"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-020-09677-1"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13432"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2019.105068"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-020-02890-4"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules17010851"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.255"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2017"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.115.066845"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-013-1634-1"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.8.7.743"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.05.116"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100072"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.051755"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.8.6.547"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2087"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2272"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1089\/jwh.2005.14.104"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.17535.1"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.2225","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T03:45:37Z","timestamp":1692503137000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.2225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6]]},"references-count":66,"journal-issue":{"issue":"S1","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1002\/jcph.2225"],"URL":"https:\/\/doi.org\/10.1002\/jcph.2225","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6]]},"assertion":[{"value":"2022-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}