{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T06:23:59Z","timestamp":1762410239420,"version":"3.41.2"},"reference-count":34,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,2,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir\/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV\u2019s influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg\/L [10 times protein binding-adjusted EC\n            <jats:sub>50<\/jats:sub>\n            for wild-type (WT) HIV-1] and 0.0243 mg\/L (10 times EC\n            <jats:sub>90<\/jats:sub>\n            for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800\/100 mg DRV\/r once a day. Administration of 800\/100 mg of DRV\/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older.\n          <\/jats:p>","DOI":"10.1128\/aac.01004-23","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T14:04:06Z","timestamp":1702303446000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents: a substudy of the SMILE trial"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6195-1502","authenticated-orcid":true,"given":"Seef","family":"Abdalla","sequence":"first","affiliation":[{"name":"Pharmacologie et \u00e9valuation des th\u00e9rapeutiques chez l'enfant et la femme enceinte, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Service de Pharmacologie Clinique, H\u00f4pital Cochin, APHP Centre\u2013Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Compagnucci","sequence":"additional","affiliation":[{"name":"SC10-US019 Essais Th\u00e9rapeutiques et Maladies Infectieuses, INSERM, Villejuif, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoann","family":"Riault","sequence":"additional","affiliation":[{"name":"SC10-US019 Essais Th\u00e9rapeutiques et Maladies Infectieuses, INSERM, Villejuif, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man K.","family":"Chan","sequence":"additional","affiliation":[{"name":"MRC Clinical Trials Unit at UCL, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alasdair","family":"Bamford","sequence":"additional","affiliation":[{"name":"MRC Clinical Trials Unit at UCL, London, United Kingdom"},{"name":"Paediatric Infectious Diseases, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aoife","family":"Nolan","sequence":"additional","affiliation":[{"name":"MRC Clinical Trials Unit at UCL, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 T.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fundaci\u00f3n de Investigaci\u00f3n Biom\u00e9dica Hospital Cl\u00ednico San Carlos, Hospital Cl\u00ednico San Carlos, Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Infecciosas, Universidad Complutense de Madrid, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentin","family":"Constant","sequence":"additional","affiliation":[{"name":"Pharmacologie et \u00e9valuation des th\u00e9rapeutiques chez l'enfant et la femme enceinte, Universit\u00e9 Paris Cit\u00e9, Paris, 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France"},{"name":"Unit\u00e9 de Recherche Clinique, H\u00f4pital Necker Enfants Malades, APHP Centre\u2013Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e9o","family":"Froelicher-Bournaud","sequence":"additional","affiliation":[{"name":"Pharmacologie et \u00e9valuation des th\u00e9rapeutiques chez l'enfant et la femme enceinte, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Service de Pharmacologie Clinique, H\u00f4pital Cochin, APHP Centre\u2013Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Neveux","sequence":"additional","affiliation":[{"name":"Service de Biochimie, H\u00f4pital Cochin, APHP Centre\u2013Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yacine","family":"Saidi","sequence":"additional","affiliation":[{"name":"SC10-US019 Essais 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