Seef Abdalla, Alexandra Compagnucci, Alasdair Bamford, Man K Chan, José T Ramos, Yoann Riault, Yacine Saidi, Valentin Constant, Thao-Nguyen Nguyen, Carlo Giaquinto, Jean-Marc Tréluyer, Tim R Cressey, Déborah Hirt
{"title":"多替格拉韦和利托那韦在青少年中增强的达那韦的稳态药物相互作用评估。","authors":"Seef Abdalla, Alexandra Compagnucci, Alasdair Bamford, Man K Chan, José T Ramos, Yoann Riault, Yacine Saidi, Valentin Constant, Thao-Nguyen Nguyen, Carlo Giaquinto, Jean-Marc Tréluyer, Tim R Cressey, Déborah Hirt","doi":"10.1097/QAD.0000000000004223","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>DTG is primarily metabolized by the UDP-glycosyltransferase (UGT) 1A1, and to a lesser extent by the cytochrome P450 (CYP) 3A4. Co-administration of DRV/r has been reported to decrease DTG plasma concentrations. Our aim was to distinguish the extent of the drug-drug interactions between DRV/r and DTG, and to evaluate the consequences of this interaction, in adolescents at steady state.</p><p><strong>Design: </strong>SMILE (PENTA 17-ANRS152) was a phase II/III trial assessing the safety and efficacy of once-daily dual therapy, using dolutegravir (DTG) combined with ritonavir-boosted darunavir (DRV/r), in virologically suppressed adolescents aged 12 years and older.</p><p><strong>Methods: </strong>A joint population pharmacokinetic model for DTG and DRV/r was developed with prior individual drug models (involving unbound and total concentrations) using SMILE data.</p><p><strong>Results: </strong>Unbound DRV exposure, integrated as a power function on unbound DTG clearance best described DRV/r inhibition of DTG elimination. Nevertheless, no interaction was identified between DRV/r and total DTG clearance. Moreover, the influence of unbound DRV exposures to predict unbound DTG concentrations was relatively small.</p><p><strong>Conclusion: </strong>Administration of DRV/r 800/100 mg and DTG 50 mg once daily provides adequate concentrations and exposures with no clinically relevant drug-drug interactions at steady-state.</p>","PeriodicalId":7502,"journal":{"name":"AIDS","volume":" ","pages":"1385-1391"},"PeriodicalIF":3.4000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Assessment of the steady-state drug-drug interactions between dolutegravir and ritonavir-boosted darunavir in adolescents.\",\"authors\":\"Seef Abdalla, Alexandra Compagnucci, Alasdair Bamford, Man K Chan, José T Ramos, Yoann Riault, Yacine Saidi, Valentin Constant, Thao-Nguyen Nguyen, Carlo Giaquinto, Jean-Marc Tréluyer, Tim R Cressey, Déborah Hirt\",\"doi\":\"10.1097/QAD.0000000000004223\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>DTG is primarily metabolized by the UDP-glycosyltransferase (UGT) 1A1, and to a lesser extent by the cytochrome P450 (CYP) 3A4. Co-administration of DRV/r has been reported to decrease DTG plasma concentrations. Our aim was to distinguish the extent of the drug-drug interactions between DRV/r and DTG, and to evaluate the consequences of this interaction, in adolescents at steady state.</p><p><strong>Design: </strong>SMILE (PENTA 17-ANRS152) was a phase II/III trial assessing the safety and efficacy of once-daily dual therapy, using dolutegravir (DTG) combined with ritonavir-boosted darunavir (DRV/r), in virologically suppressed adolescents aged 12 years and older.</p><p><strong>Methods: </strong>A joint population pharmacokinetic model for DTG and DRV/r was developed with prior individual drug models (involving unbound and total concentrations) using SMILE data.</p><p><strong>Results: </strong>Unbound DRV exposure, integrated as a power function on unbound DTG clearance best described DRV/r inhibition of DTG elimination. Nevertheless, no interaction was identified between DRV/r and total DTG clearance. Moreover, the influence of unbound DRV exposures to predict unbound DTG concentrations was relatively small.</p><p><strong>Conclusion: </strong>Administration of DRV/r 800/100 mg and DTG 50 mg once daily provides adequate concentrations and exposures with no clinically relevant drug-drug interactions at steady-state.</p>\",\"PeriodicalId\":7502,\"journal\":{\"name\":\"AIDS\",\"volume\":\" \",\"pages\":\"1385-1391\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"AIDS\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/QAD.0000000000004223\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/2 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"AIDS","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/QAD.0000000000004223","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/2 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Assessment of the steady-state drug-drug interactions between dolutegravir and ritonavir-boosted darunavir in adolescents.
Objectives: DTG is primarily metabolized by the UDP-glycosyltransferase (UGT) 1A1, and to a lesser extent by the cytochrome P450 (CYP) 3A4. Co-administration of DRV/r has been reported to decrease DTG plasma concentrations. Our aim was to distinguish the extent of the drug-drug interactions between DRV/r and DTG, and to evaluate the consequences of this interaction, in adolescents at steady state.
Design: SMILE (PENTA 17-ANRS152) was a phase II/III trial assessing the safety and efficacy of once-daily dual therapy, using dolutegravir (DTG) combined with ritonavir-boosted darunavir (DRV/r), in virologically suppressed adolescents aged 12 years and older.
Methods: A joint population pharmacokinetic model for DTG and DRV/r was developed with prior individual drug models (involving unbound and total concentrations) using SMILE data.
Results: Unbound DRV exposure, integrated as a power function on unbound DTG clearance best described DRV/r inhibition of DTG elimination. Nevertheless, no interaction was identified between DRV/r and total DTG clearance. Moreover, the influence of unbound DRV exposures to predict unbound DTG concentrations was relatively small.
Conclusion: Administration of DRV/r 800/100 mg and DTG 50 mg once daily provides adequate concentrations and exposures with no clinically relevant drug-drug interactions at steady-state.
期刊介绍：
Publishing the very latest ground breaking research on HIV and AIDS. Read by all the top clinicians and researchers, AIDS has the highest impact of all AIDS-related journals. With 18 issues per year, AIDS guarantees the authoritative presentation of significant advances. The Editors, themselves noted international experts who know the demands of your work, are committed to making AIDS the most distinguished and innovative journal in the field. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.
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