{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:28:44Z","timestamp":1787016524394,"version":"build-2736575974"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,4,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. People living with HIV are at risk of liver disease. ISL is metabolized by adenosine deaminase (ADA), which is expressed in the liver; thus, ISL pharmacokinetics (PK) may be affected by hepatic impairment. This study evaluated the effect of moderate hepatic impairment on ISL PK. This nonrandomized, open-label, phase 1 study (MK-8591-030) evaluated the effects of a single oral dose of ISL 60 mg in HIV-seronegative adults with moderate hepatic insufficiency (\n                      <jats:italic>n<\/jats:italic>\n                      = 6) and matched healthy adult participants (\n                      <jats:italic>n<\/jats:italic>\n                      = 6). Blood samples for plasma ISL and 4\u2032-ethynyl-2-fluoro-2\u2032deoxyinosine (M4) and peripheral blood mononuclear cell (PBMC) ISL-triphosphate (ISL-TP) were collected at multiple time points through 672 h, and safety was monitored throughout. Modest decreases in maximum measured concentration (\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      ) and area under the concentration-time curve (AUC) of plasma ISL and AUC of PBMC ISL-TP were observed in participants with moderate hepatic impairment versus matched healthy participants, while ISL-TP\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      was relatively unchanged. In contrast, plasma M4 was modestly increased in the moderate hepatic impairment group, suggesting that hepatic impairment may result in increased metabolism of ISL to M4 via ADA. The clinical relevance of the overall modest changes in M4, ISL, and ISL-TP levels with moderate hepatic impairment will be contextualized once exposure response data from ongoing clinical studies are available to elucidate the thresholds for clinical efficiency. A single oral dose of ISL 60 mg was generally well tolerated in both groups.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>CLINICAL TRIALS<\/jats:title>\n                      <jats:p>\n                        This study is registered with Clinicaltrials.gov as\n                        <jats:related-object xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" document-id=\"NCT04515641\" document-id-type=\"clinical-trial-number\" source-id=\"ClinicalTrials.gov\" source-id-type=\"registry-name\" source-type=\"clinical-trials-registry\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04515641\">NCT04515641<\/jats:related-object>\n                        .\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01553-24","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T09:00:24Z","timestamp":1741165224000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetics of islatravir in participants with moderate hepatic impairment"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8403-267X","authenticated-orcid":true,"given":"Randolph P.","family":"Matthews","sequence":"first","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6892-0899","authenticated-orcid":false,"given":"Munjal","family":"Patel","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Rond\u00f3n","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology of Miami","place":["Hialeah, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C.","family":"Vargo","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Aubrey","family":"Stoch","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["Rahway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"Joint United Nations Programme on HIV\/AIDS. 2024. UNAIDS 2023 Fact Sheet - Global HIV statistics. Available from: https:\/\/www.unaids.org\/sites\/default\/files\/media_asset\/UNAIDS_FactSheet_en.pdf. Retrieved 24 Feb 2025."},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61809-7"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clindermatol.2024.02.001"},{"key":"e_1_3_5_5_2","unstructured":"National Institute of Allergy and Infectious Diseases. 2025. Antiretroviral drug discovery and development. 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Accessed 2414 FebJanuary 2025"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00931-22"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00270-09"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00277-07"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05036-14"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00723-12"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.857"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01344-23"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01553-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01553-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T01:36:29Z","timestamp":1743730589000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01553-24"}},"subtitle":[],"editor":[{"given":"Miguel Angel","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,2]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,2]]}},"alternative-id":["10.1128\/aac.01553-24"],"URL":"https:\/\/doi.org\/10.1128\/aac.01553-24","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,2]]},"assertion":[{"value":"2024-10-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01553-24"}}