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Physiologically\u2010based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if <jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub> was maintained above cabotegravir and rilpivirine target concentrations (664 and 50\u2009ng\/mL, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy\u2010induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long\u2010acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Predicted <jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub> at week 12 for monthly long\u2010acting cabotegravir was above 664\u2009ng\/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long\u2010acting cabotegravir. Predicted <jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub> at week 12 for monthly and bimonthly long\u2010acting rilpivirine was below 50\u2009ng\/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord\u2010to\u2010maternal blood ratios were 1.71 (range, 1.55\u20101.79) for cabotegravir and 0.88 (0.78\u20100.93) for rilpivirine between weeks 38 and 40.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Model predictions suggest that monthly long\u2010acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long\u2010acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16006","type":"journal-article","created":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T11:19:11Z","timestamp":1707563951000},"page":"989-1002","source":"Crossref","is-referenced-by-count":27,"title":["Physiologically\u2010based pharmacokinetic modelling of long\u2010acting injectable cabotegravir and rilpivirine in pregnancy"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1393-3753","authenticated-orcid":false,"given":"Shakir","family":"Atoyebi","sequence":"first","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fazila","family":"Bunglawala","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Cottura","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Gra\u00f1ana\u2010Castillo","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-360X","authenticated-orcid":false,"given":"Maiara Camotti","family":"Montanha","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8902-4150","authenticated-orcid":false,"given":"Adeniyi","family":"Olagunju","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Siccardi","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0134-5855","authenticated-orcid":false,"given":"Catriona","family":"Waitt","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,10]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"Global HIV & AIDS statistics\u2014fact sheet","author":"UNAIDS","year":"2022"},{"key":"e_1_2_11_3_1","volume-title":"Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach","author":"WHO","year":"2016"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352\u20103018(19)30236\u2010X"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.1818"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002015"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11136\u2010021\u201002889\u2010z"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.5769"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.2147\/CIA.S121905"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/ppe.12705"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1086\/313849"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab324"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2018.1453805"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.107"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010021\u201001005\u20101"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2192"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612825666190320162507"},{"key":"e_1_2_11_18_1","unstructured":"ViiV Healthcare.CABENUVA (cabotegravir extended\u2010release injectable suspension; rilpivirine extended\u2010release injectable suspension). 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