Lisanne A H Bevers, Gabriela Toledo, Muzamil Kisekka, Elizabeth Kaudha, Grace M Ahimbisibwe, Isabelle Deprez, Tiyara Arumugan, Ebrahim Variava, Avy Violari, Iona White, Dickson Bbuye, Annet Nanduudu, Enoch Mulwanyi, Pauline Amuge, Diana A Rutebarika, Adeodata Kekitiinwa, Cissy Kityo, Philippa Musoke, Moherndran Archary, Justine Boles, Margaret J Thomason, Saskia N de Wildt, Carlo Giaquinto, Angela Colbers, David M Burger, Ann M Buchanan, Man K Chan, Tom G Jacobs, Anna Turkova
{"title":"每日一次的多替格拉韦/拉米夫定固定剂量制剂在艾滋病毒感染儿童中的应用：一项开放标签、多中心、随机、非劣效性D3/PENTA 21试验的药代动力学和安全性亚研究","authors":"Lisanne A H Bevers, Gabriela Toledo, Muzamil Kisekka, Elizabeth Kaudha, Grace M Ahimbisibwe, Isabelle Deprez, Tiyara Arumugan, Ebrahim Variava, Avy Violari, Iona White, Dickson Bbuye, Annet Nanduudu, Enoch Mulwanyi, Pauline Amuge, Diana A Rutebarika, Adeodata Kekitiinwa, Cissy Kityo, Philippa Musoke, Moherndran Archary, Justine Boles, Margaret J Thomason, Saskia N de Wildt, Carlo Giaquinto, Angela Colbers, David M Burger, Ann M Buchanan, Man K Chan, Tom G Jacobs, Anna Turkova","doi":"10.1016/j.ebiom.2025.105929","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Two-drug regimen dolutegravir/lamivudine (DTG/3TC) is recommended as an alternative to standard three-drug regimens in adult treatment guidelines. This nested pharmacokinetic sub-study within the D3/Penta 21 randomised trial (#NCT04337450) assessed DTG and 3TC concentrations and safety in virologically-suppressed children, switching to once-daily DTG/3TC fixed-dose formulations.</p><p><strong>Methods: </strong>Children aged 2-<15 years received either 5/30 mg DTG/3TC dispersible tablets (DT) or 50/300 mg film-coated tablets (FCT), using WHO weight band (WB)-aligned dosing: 10-<14 kg 4 DTs; 14-<20 kg 5 DTs; 20-<25 kg 6 DTs or 1 FCT; 25-<40 kg 1 FCT. A minimum of 8-evaluable pharmacokinetic curves per WB/formulation were targeted for 24 h pharmacokinetic profiling (t = 0, 1, 2, 3, 4, 6, and 24 h post-dosing) at steady state. The number of children with DTG C<sub>trough</sub> <0.32 mg/L (EC90) and <0.064 mg/L (PA-IC90) were summarised. Safety was evaluated through 48 weeks in eligible children consented to the pharmacokinetic sub-study.</p><p><strong>Findings: </strong>Between 11th May 2022 and 31st May 2023, 82 children consented for the sub-study. Seventy-two were included in the pharmacokinetic analysis; median (IQR) age was 7.1 (4.9-10.0) years and weight 21.6 (17.7-24.8) kg. DTG geometric mean (GM) (%CV) C<sub>trough</sub> and AUC<sub>0-24 h</sub> were 0.82 (54) mg/L and 66.2 (35) h∗mg/L. 3TC GM-AUC<sub>0-24 h</sub> was 16.2 (45) h∗mg/L. Three children had DTG C<sub>trough</sub><0.32 mg/L, all had DTG C<sub>trough</sub> ≥0.064 mg/L. In children weighing 20-<25 kg WB and taking 1 FCT (50/300 mg) 3TC GM AUC<sub>0-24 h</sub> was 19% higher than in children ≥25 kg (1 FCT). Of 82 children, 3 had 4 serious adverse events (SAEs) and 5 had 6 grade ≥3 adverse events (AEs). No AEs were related to DTG/3TC or resulted in treatment discontinuation. No 3TC-related AEs or laboratory abnormalities were observed in children taking FCT in the 20-<25 kg WB. PK parameters were comparable to historical paediatric data from ODYSSEY (DTG) and IMPAACT2019 (3TC) trials.</p><p><strong>Interpretation: </strong>The study demonstrated adequate DTG and 3TC exposures with reassuring safety profiles using WB-based dosing, supporting licencing applications for dispersible and film-coated DTG/3TC formulations for paediatric use.</p><p><strong>Funding: </strong>The D3/Penta 21 trial is sponsored by Fondazione Penta Onlus ETS (Penta) and funded by ViiV Healthcare.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105929"},"PeriodicalIF":10.8000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509724/pdf/","citationCount":"0","resultStr":"{\"title\":\"Once-daily dolutegravir/lamivudine fixed-dose formulations in children living with HIV: a pharmacokinetic and safety sub-study nested in the open-label, multicentre, randomised, non-inferiority D3/PENTA 21 trial.\",\"authors\":\"Lisanne A H Bevers, Gabriela Toledo, Muzamil Kisekka, Elizabeth Kaudha, Grace M Ahimbisibwe, Isabelle Deprez, Tiyara Arumugan, Ebrahim Variava, Avy Violari, Iona White, Dickson Bbuye, Annet Nanduudu, Enoch Mulwanyi, Pauline Amuge, Diana A Rutebarika, Adeodata Kekitiinwa, Cissy Kityo, Philippa Musoke, Moherndran Archary, Justine Boles, Margaret J Thomason, Saskia N de Wildt, Carlo Giaquinto, Angela Colbers, David M Burger, Ann M Buchanan, Man K Chan, Tom G Jacobs, Anna Turkova\",\"doi\":\"10.1016/j.ebiom.2025.105929\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Two-drug regimen dolutegravir/lamivudine (DTG/3TC) is recommended as an alternative to standard three-drug regimens in adult treatment guidelines. This nested pharmacokinetic sub-study within the D3/Penta 21 randomised trial (#NCT04337450) assessed DTG and 3TC concentrations and safety in virologically-suppressed children, switching to once-daily DTG/3TC fixed-dose formulations.</p><p><strong>Methods: </strong>Children aged 2-<15 years received either 5/30 mg DTG/3TC dispersible tablets (DT) or 50/300 mg film-coated tablets (FCT), using WHO weight band (WB)-aligned dosing: 10-<14 kg 4 DTs; 14-<20 kg 5 DTs; 20-<25 kg 6 DTs or 1 FCT; 25-<40 kg 1 FCT. A minimum of 8-evaluable pharmacokinetic curves per WB/formulation were targeted for 24 h pharmacokinetic profiling (t = 0, 1, 2, 3, 4, 6, and 24 h post-dosing) at steady state. The number of children with DTG C<sub>trough</sub> <0.32 mg/L (EC90) and <0.064 mg/L (PA-IC90) were summarised. Safety was evaluated through 48 weeks in eligible children consented to the pharmacokinetic sub-study.</p><p><strong>Findings: </strong>Between 11th May 2022 and 31st May 2023, 82 children consented for the sub-study. Seventy-two were included in the pharmacokinetic analysis; median (IQR) age was 7.1 (4.9-10.0) years and weight 21.6 (17.7-24.8) kg. DTG geometric mean (GM) (%CV) C<sub>trough</sub> and AUC<sub>0-24 h</sub> were 0.82 (54) mg/L and 66.2 (35) h∗mg/L. 3TC GM-AUC<sub>0-24 h</sub> was 16.2 (45) h∗mg/L. Three children had DTG C<sub>trough</sub><0.32 mg/L, all had DTG C<sub>trough</sub> ≥0.064 mg/L. In children weighing 20-<25 kg WB and taking 1 FCT (50/300 mg) 3TC GM AUC<sub>0-24 h</sub> was 19% higher than in children ≥25 kg (1 FCT). Of 82 children, 3 had 4 serious adverse events (SAEs) and 5 had 6 grade ≥3 adverse events (AEs). No AEs were related to DTG/3TC or resulted in treatment discontinuation. No 3TC-related AEs or laboratory abnormalities were observed in children taking FCT in the 20-<25 kg WB. PK parameters were comparable to historical paediatric data from ODYSSEY (DTG) and IMPAACT2019 (3TC) trials.</p><p><strong>Interpretation: </strong>The study demonstrated adequate DTG and 3TC exposures with reassuring safety profiles using WB-based dosing, supporting licencing applications for dispersible and film-coated DTG/3TC formulations for paediatric use.</p><p><strong>Funding: </strong>The D3/Penta 21 trial is sponsored by Fondazione Penta Onlus ETS (Penta) and funded by ViiV Healthcare.</p>\",\"PeriodicalId\":11494,\"journal\":{\"name\":\"EBioMedicine\",\"volume\":\"120 \",\"pages\":\"105929\"},\"PeriodicalIF\":10.8000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509724/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EBioMedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ebiom.2025.105929\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/9/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2025.105929","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/9/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Once-daily dolutegravir/lamivudine fixed-dose formulations in children living with HIV: a pharmacokinetic and safety sub-study nested in the open-label, multicentre, randomised, non-inferiority D3/PENTA 21 trial.
Background: Two-drug regimen dolutegravir/lamivudine (DTG/3TC) is recommended as an alternative to standard three-drug regimens in adult treatment guidelines. This nested pharmacokinetic sub-study within the D3/Penta 21 randomised trial (#NCT04337450) assessed DTG and 3TC concentrations and safety in virologically-suppressed children, switching to once-daily DTG/3TC fixed-dose formulations.
Methods: Children aged 2-<15 years received either 5/30 mg DTG/3TC dispersible tablets (DT) or 50/300 mg film-coated tablets (FCT), using WHO weight band (WB)-aligned dosing: 10-<14 kg 4 DTs; 14-<20 kg 5 DTs; 20-<25 kg 6 DTs or 1 FCT; 25-<40 kg 1 FCT. A minimum of 8-evaluable pharmacokinetic curves per WB/formulation were targeted for 24 h pharmacokinetic profiling (t = 0, 1, 2, 3, 4, 6, and 24 h post-dosing) at steady state. The number of children with DTG Ctrough <0.32 mg/L (EC90) and <0.064 mg/L (PA-IC90) were summarised. Safety was evaluated through 48 weeks in eligible children consented to the pharmacokinetic sub-study.
Findings: Between 11th May 2022 and 31st May 2023, 82 children consented for the sub-study. Seventy-two were included in the pharmacokinetic analysis; median (IQR) age was 7.1 (4.9-10.0) years and weight 21.6 (17.7-24.8) kg. DTG geometric mean (GM) (%CV) Ctrough and AUC0-24 h were 0.82 (54) mg/L and 66.2 (35) h∗mg/L. 3TC GM-AUC0-24 h was 16.2 (45) h∗mg/L. Three children had DTG Ctrough<0.32 mg/L, all had DTG Ctrough ≥0.064 mg/L. In children weighing 20-<25 kg WB and taking 1 FCT (50/300 mg) 3TC GM AUC0-24 h was 19% higher than in children ≥25 kg (1 FCT). Of 82 children, 3 had 4 serious adverse events (SAEs) and 5 had 6 grade ≥3 adverse events (AEs). No AEs were related to DTG/3TC or resulted in treatment discontinuation. No 3TC-related AEs or laboratory abnormalities were observed in children taking FCT in the 20-<25 kg WB. PK parameters were comparable to historical paediatric data from ODYSSEY (DTG) and IMPAACT2019 (3TC) trials.
Interpretation: The study demonstrated adequate DTG and 3TC exposures with reassuring safety profiles using WB-based dosing, supporting licencing applications for dispersible and film-coated DTG/3TC formulations for paediatric use.
Funding: The D3/Penta 21 trial is sponsored by Fondazione Penta Onlus ETS (Penta) and funded by ViiV Healthcare.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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