{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T17:40:48Z","timestamp":1788716448618,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Oral pre\u2010exposure prophylaxis (PrEP) can substantially reduce HIV infection risk when taken as prescribed. However, many individuals struggle adhering to the daily regimen. Twice\u2010yearly injections of the novel HIV capsid inhibitor lenacapavir (LEN) demonstrated potential in recent PrEP trials. However, clinical trials may not enable us to accurately estimate efficacy or protective concentration benchmarks. Moreover, while LEN can persist for more than a year, stopping PrEP may facilitate de novo drug resistance emergence. We developed an integrated PK\u2010PD model of LEN, incorporating PK variability to quantify prophylactic efficacy against wild\u2010type virus and transmitted drug resistance and to estimate the probability of drug resistance emergence when LEN\u2010PrEP is stopped. We estimated a 95% preventive and fully preventive plasma concentration of 4.7\u2009ng\/mL and \u20095\u2009ng\/mL, respectively. The latter was reached within 23\u2009h after the first 927\u2009mg LEN SC injection and maintained up to 50.5\u2009weeks after the last dose in an \u2018average\u2019 individual. Considering PK\u2010variability, concentrations of \u20095\u2009ng\/mL were not consistently maintained at all times especially considering lower concentration ranges, but were surpassed at steady\u2010state. Full protection was achieved at 21, 59, 1108, 142, 538, 107, 1142\u2009ng\/mL for viruses carrying mutations Q67H, N74D, Q67H\u2009+\u2009N74D, Q67H\u2009+\u2009T107N, M66I\u2009+\u2009T107A, Q67H\u2009+\u2009K70R, Q67H\u2009+\u2009K70R\u2009+\u2009T107N, respectively, and mutant selection windows for N74D, all double mutants and Q67H\u2009+\u2009K70R\u2009+\u2009T107N overlapped with LEN SC steady\u2010state concentrations. In an \u2018average\u2019 individual, wild\u2010type infection with subsequent de novo resistance emergence may occur within a period of 206, 170, 138, 160, 106, 191, 235\u2009days for Q67H, N74D, Q67H\u2009+\u2009N74D, Q67H\u2009+\u2009T107N, M66I\u2009+\u2009T107A, Q67H\u2009+\u2009K70R, Q67H\u2009+\u2009K70R\u2009+\u2009T107N after stopping LEN\u2010injections, calling for strategies to manage LEN\u2010PrEP discontinuation.<\/jats:p>","DOI":"10.1002\/psp4.70254","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:21:28Z","timestamp":1776673288000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacokinetics, Pharmacodynamics, Efficacy and Drug Resistance Selection of Injectable Long\u2010Acting Lenacapavir Pre\u2010Exposure Prophylaxis (\n                    <scp>PrEP<\/scp>\n                    ) Against\n                    <scp>HIV<\/scp>"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9060-8953","authenticated-orcid":false,"given":"Hee\u2010yeong","family":"Kim","sequence":"first","affiliation":[{"name":"Project Group 5 \u201cSystems Medicine of Infectious Disease\u201d, Robert Koch Institute  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Liebenberg","sequence":"additional","affiliation":[{"name":"Project Group 5 \u201cSystems Medicine of Infectious Disease\u201d, Robert Koch Institute  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3740-4450","authenticated-orcid":false,"given":"Lanxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Project Group 5 \u201cSystems Medicine of Infectious Disease\u201d, Robert Koch Institute  Berlin Germany"},{"name":"Mathematics for Data Science, Dep. of Mathematics and Computer Science Freie Universit\u00e4t Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-6394","authenticated-orcid":false,"given":"Max","family":"von Kleist","sequence":"additional","affiliation":[{"name":"Project Group 5 \u201cSystems Medicine of Infectious Disease\u201d, Robert Koch Institute  Berlin Germany"},{"name":"Mathematics for Data Science, Dep. of Mathematics and Computer Science Freie Universit\u00e4t Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"UNAIDS \u201cFact Sheet 2024\u2014Latest Global and Regional Hiv Statistics \u201d(2024) https:\/\/www.unaids.org\/sites\/default\/files\/media_asset\/UNAIDS_FactSheet_en.pdf."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(23)00028-0"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.044"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(22)00029-7"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciad021"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijregi.2022.08.009"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2407001"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2101016"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00538-4"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13212"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2411858"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02615-x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(18)30045-6"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2025.117125"},{"key":"e_1_2_10_16_1","first-page":"ofae468","volume-title":"Open Forum Infectious Diseases","author":"Koss C. 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