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The present work aimed to characterize the viral response based on a pooled analysis of exposure\u2013response (E\u2013R) from five studies in treatment\u2010experienced and integrase\u2010resistant (INI\u2010r) patients infected with HIV\u20101. Importantly, model\u2010based simulations of the E\u2013R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub\u2010population with Q148\u2010driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation\u2010containing products) factors expected to influence the DTG E\u2013R relationship. Model\u2010based <jats:italic>post hoc<\/jats:italic> exposure metrics (<jats:italic>C<\/jats:italic>\n<jats:sub>min<\/jats:sub> and <jats:italic>C<\/jats:italic>\n<jats:sub>avg<\/jats:sub>) were incorporated into a mechanistic population viral dynamic model describing the short\u2010term effect of DTG on log10 HIV\u20101 RNA viral load over 8 or 10\u2009days. In addition, the impact of DTG in combination with background ARTs on the 24\u2010week HIV RNA response was also assessed using logistic regression. There was good concordance between model\u2010based predictions and observed virologic response on day 10 and week 24. The E\u2013R model\u2010based simulations exploring the potential impact of a higher dose (100\u2009mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50\u2009mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50\u2009mg b.i.d. in the integrase inhibitor\u2010resistant (INI\u2010r) population.<\/jats:p>","DOI":"10.1002\/cpt.3370","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T04:40:25Z","timestamp":1721191225000},"page":"1100-1109","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Population Exposure\u2013Response of Dolutegravir in HIV\u20101 Supports Bridging of Clinical Response Influenced by Relevant Intrinsic and Extrinsic Patient Characteristics"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1289-0800","authenticated-orcid":false,"given":"Hardik","family":"Chandasana","sequence":"first","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0040-7957","authenticated-orcid":false,"given":"Mark","family":"Bush","sequence":"additional","affiliation":[{"name":"ViiV Healthcare  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy","family":"Vavro","sequence":"additional","affiliation":[{"name":"ViiV Healthcare  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny","family":"Huang","sequence":"additional","affiliation":[{"name":"GSK  Mississauga Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mounir","family":"Ait\u2010Khaled","sequence":"additional","affiliation":[{"name":"ViiV Healthcare Ltd  Brentford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Wynne","sequence":"additional","affiliation":[{"name":"ViiV Healthcare  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherene","family":"Min","sequence":"additional","affiliation":[{"name":"ViiV Healthcare  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashmi","family":"Mehta","sequence":"additional","affiliation":[{"name":"GSK  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01209-10"},{"key":"e_1_2_9_2_1","unstructured":"TIVICAY.(Dolutegravir) [package insert]. Research Triangle Park (NC): ViiV Healthcare(2021)."},{"key":"e_1_2_9_3_1","unstructured":"TIVICAY.(Dolutegravir) [SUMMARY OF PRODUCT CHARACTERISTICS](2021)."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e32834a1dd9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e3283612419"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61221-0"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu051"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2878"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis750"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15122426"},{"key":"e_1_2_9_11_1","unstructured":"FDA review dolutegravir.Clinical Pharmacology and Biopharmaceutics Reviews(s). <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2013\/204790Orig1s000ClinPharmR.pdf> (2012). 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