{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:42:18Z","timestamp":1792208538721,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 AI157853"],"award-info":[{"award-number":["R21 AI157853"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011072","name":"Center for AIDS Research, University of North Carolina at Chapel Hill","doi-asserted-by":"publisher","award":["P30 AI050410"],"award-info":[{"award-number":["P30 AI050410"]}],"id":[{"id":"10.13039\/100011072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:p>\n                    Romidepsin (RMD), an FDA\u2010approved histone deacetylase inhibitor for treating cancer, demonstrates potent latency\u2010reversing activity\n                    <jats:italic>in vitro<\/jats:italic>\n                    but has yielded suboptimal outcomes in kick\u2010and\u2010kill HIV\u2010cure trials when administered as a 5\u2009mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    infusion. We hypothesized that distinct pharmacokinetic targets exist between the pharmacodynamic goals of cytotoxicity for cancer therapy and latency reversal for HIV cure. To address this question, we designed an empirical modeling framework incorporating patient pharmacokinetics as a New Approach Methodology. Using clonal\u2010 and primary cell models of HIV\u20101 latency with readouts for different stages of latency\u2010reversing activity, we performed exposure\u2013response and dose\u2010fractionation studies to define pharmacokinetic drivers of efficacy in latency, then designed tailored dosing strategies to meet these targets in static\u2010 and dynamic\u2010culture systems, including a hollow\u2010fiber model. Across all systems, the only consistent pharmacokinetic parameter driving latency\u2010reversing activity, was RMD exposure time, with maximal activity achieved in cells exposed to ~4\u20136\u2009ng\/mL RMD for \u2265\u200920\u2009hours (AUCs of ~80\u2013120\u2009ng*hour\/mL). With current clinical\u2010dosing strategies achieving AUCs of 240\u2013600\u2009ng*hour\/mL, the same outcome occurred only when RMD concentrations greatly exceeded a cytotoxicity threshold, suggesting response was a byproduct of cytotoxic processes rather than targeted latency reversal. These findings indicate that conventional oncologic dosing strategies for RMD might not be directly applicable to HIV\u20101 latency reversal, offering a mechanistic explanation for suboptimal clinical outcomes. We provide proof\u2010of\u2010concept for RMD's limited clinical efficacy and propose a \u201clow and slow\u201d dosing strategy targeting time\u2010driven, toxicity\u2010minimized drug exposure, demonstrating how\n                    <jats:italic>in vitro<\/jats:italic>\n                    pharmacokinetic\/pharmacodynamic investigations applying clinical pharmacokinetic data may inform dose optimization for clinical trials of latency reversal.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70488","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:41:53Z","timestamp":1790574113000},"page":"1414-1426","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Empirical\n                    <scp>PK<\/scp>\n                    \/\n                    <scp>PD<\/scp>\n                    Model for Differentiating Intrinsic Dosing Rules by Therapeutic Indication With Relevance for HIV\u20101 Latency Reversal"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8503-9686","authenticated-orcid":false,"given":"Lauren A. R.","family":"Tompkins","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"UNC HIV Cure Center University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0150-0500","authenticated-orcid":false,"given":"Amanda","family":"Poliseno","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7378-7587","authenticated-orcid":false,"given":"Airlie","family":"Ward","sequence":"additional","affiliation":[{"name":"UNC HIV Cure Center University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Institute for Global Health and Infectious Diseases, UNC School of Medicine University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9070-7015","authenticated-orcid":false,"given":"Edward P.","family":"Browne","sequence":"additional","affiliation":[{"name":"UNC HIV Cure Center University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Institute for Global Health and Infectious Diseases, UNC School of Medicine University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9372-2784","authenticated-orcid":false,"given":"Craig","family":"Sykes","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9171-8493","authenticated-orcid":false,"given":"Angela D. M.","family":"Kashuba","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"UNC HIV Cure Center University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0291-5111","authenticated-orcid":false,"given":"Mackenzie L.","family":"Cottrell","sequence":"additional","affiliation":[{"name":"Department of Pharmacy: Clinical &amp; Administrative Sciences University of Oklahoma College of Pharmacy  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-050520-112001"},{"key":"e_1_2_10_2_1","first-page":"229","article-title":"Chromatin regulation and the histone code in HIV latency","volume":"90","author":"Turner A.M.W.","year":"2017","journal-title":"Yale J. 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