{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T01:01:17Z","timestamp":1787187677144,"version":"build-2736575974"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T00:00:00Z","timestamp":1689638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council, Australia","award":["APP1117470"],"award-info":[{"award-number":["APP1117470"]}]},{"name":"National Health and Medical Research Council, Australia","award":["APP1103050"],"award-info":[{"award-number":["APP1103050"]}]},{"name":"Australian Government Research Training Program (RTP) PhD Scholarship","award":["APP1117470"],"award-info":[{"award-number":["APP1117470"]}]},{"name":"Australian Government Research Training Program (RTP) PhD Scholarship","award":["APP1103050"],"award-info":[{"award-number":["APP1103050"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>N-(4-hydroxyphenyl) retinamide (4-HPR, or fenretinide) has promising in vitro and in vivo antiviral activity against a range of flaviviruses and an established safety record, but there are challenges to its clinical use. This study evaluated the in vivo exposure profile of a 4-HPR dosage regime previously shown to be effective in a mouse model of severe dengue virus (DENV) infection, comparing it to an existing formulation for human clinical use for other indications and developed\/characterised self-emulsifying lipid-based formulations of 4-HPR to enhance 4-HPR in vivo exposure. Pharmacokinetic (PK) analysis comprising single-dose oral and IV plasma concentration-time profiles was performed in mice; equilibrium solubility testing of 4-HPR in a range of lipids, surfactants and cosolvents was used to inform formulation approaches, with lead formulation candidates digested in vitro to analyse solubilisation\/precipitation prior to in vivo testing. PK analysis suggested that effective plasma concentrations could be achieved with the clinical formulation, while novel lipid-based formulations achieved &gt; 3-fold improvement. Additionally, 4-HPR exposure was found to be limited by both solubility and first-pass intestinal elimination but could be improved through inhibition of cytochrome P450 (CYP) metabolism. Simulated exposure profiles suggest that a b.i.d dosage regime is likely to maintain 4-HPR above the minimum effective plasma concentration for anti-DENV activity using the clinical formulation, with new formulations\/CYP inhibition viable options to increase exposure in the future.<\/jats:p>","DOI":"10.3390\/pharmaceutics15071974","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:54:01Z","timestamp":1689728041000},"page":"1974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Increased In Vivo Exposure of N-(4-Hydroxyphenyl) Retinamide (4-HPR) to Achieve Plasma Concentrations Effective against Dengue Virus"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-8762","authenticated-orcid":false,"given":"Alexander J.","family":"Martin","sequence":"first","affiliation":[{"name":"Nuclear Signalling Laboratory, Department Biochem. & Mol. Biol., Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Shackleford","sequence":"additional","affiliation":[{"name":"Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Charman","sequence":"additional","affiliation":[{"name":"Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie M.","family":"Wagstaff","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department Biochem. & Mol. Biol., Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3474-7551","authenticated-orcid":false,"given":"Christopher J. H.","family":"Porter","sequence":"additional","affiliation":[{"name":"Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5115-4745","authenticated-orcid":false,"given":"David A.","family":"Jans","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department Biochem. & Mol. Biol., Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, October 05). WHO Coronavirus (COVID-19) Dashboard. Available online: https:\/\/covid19.who.int."},{"key":"ref_2","unstructured":"World Health Organization (2022, October 05). Estimated Number of People (All Ages) Living with HIV. 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