Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1–2 trial,The Lancet HIV

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Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1–2 trial
The Lancet HIV ( IF 12.8 ) Pub Date : 2022-04-27 , DOI: 10.1016/s2352-3018(22)00044-3
Theodore D Ruel ₁ , Edward P Acosta ₂ , Jessica P Liu ₃ , Kathryn P Gray ₄ , Kathleen George ₅ , Nicole Montañez ₅ , Stephanie Popson ₆ , Ann M Buchanan ₇ , Mattie Bartlett ₆ , Dale Dayton ₈ , Patricia Anthony ₉ , Cynthia Brothers ₇ , Cynthia Vavro ₇ , Rajendra Singh ₁₀ , Lucy Koech ₁₁ , Tichaona Vhembo ₁₂ , Blandina T Mmbaga ₁₃ , Jorge A Pinto ₁₄ , Els F M Dobbels ₁₅ , Moherndran Archary ₁₆ , Kulkanya Chokephaibulkit ₁₇ , Pradthana Ounchanum ₁₈ , Jaime G Deville ₁₉ , Rohan Hazra ₂₀ , Ellen Townley ₂₁ , Andrew Wiznia ₂₂ ,

Affiliation

University of California, San Francisco, San Francisco, CA, USA.
University of Alabama at Birmingham, Birmingham, AL, USA.
Frontier Science & Technology and Research Foundation, Brookline, MA, USA.
Frontier Science & Technology and Research Foundation, Brookline, MA, USA; Harvard T H Chan School of Public Health, Boston, MA, USA.
FHI 360, Durham, NC, USA.
Frontier Science & Technology and Research Foundation, Amherst, NY, USA.
ViiV Healthcare, Research Triangle Park, NC, USA.
University of California, Los Angeles, Los Angeles, CA, USA.
University of Southern California, Los Angeles, CA, USA.
GlaxoSmithKline, Collegeville, PA, USA.
Kenya Medical Research Institute-Walter Reed Project, Kericho, Kenya.
University of Zimbabwe, Clinical Trials Research Centre, Harare, Zimbabwe.
Kilimanjaro Christian Medical Center, and Kilimanjaro Christian Medical University College, Moshi, Tanzania.
Federal University of Minas Gerais, Belo Horizonte, Brazil.
Stellenbosch University, Stellenbosch, South Africa.
CAPRISA Umlazi CTU, Durban, South Africa.
Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand.
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, NY, USA.

Background

Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children.

Methods

International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1–2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5–10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing.

Findings

We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum–maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log₁₀ copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir.

Interpretation

In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1.

Funding

National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare–GlaxoSmithKline.

中文翻译：

多替拉韦分散片在 HIV-1 婴儿和儿童中的药代动力学、安全性、耐受性和抗病毒活性 (IMPAACT P1093)：开放标签 1-2 期试验结果

背景

需要采用儿童友好配方的安全有效的抗逆转录病毒药物来治疗感染 HIV-1 的幼儿。我们的目的是选择多替拉韦分散片剂型的剂量，使其达到与成人相似的药代动力学暴露，并且在幼儿中安全且耐受性良好。

方法

国际孕产妇儿科青少年艾滋病临床试验 (IMPAACT) P1093 是一项正在进行的多替拉韦的 1-2 期多中心、开放标签、非比较研究。在 4 周至 6 岁以下、体重至少 3 kg、HIV RNA 大于 1000 拷贝/mL、且既往未接受过从 IMPAACT 招募的整合酶链转移抑制剂治疗的儿童中研究了 5 mg 多替拉韦分散片制剂非洲、美洲和亚洲的临床研究中心。根据第 5-10 天的深入药代动力学评估选择剂量，并评估长达 48 周的安全性和耐受性。本研究的主要目的是评估多替拉韦与优化背景治疗相结合的药代动力学，并确定婴儿、儿童和青少年达到目标 24 小时谷浓度和 24 小时曲线下面积的多替拉韦剂量。 HIV-1 患者，以确定 24 周和 48 周时多替拉韦的安全性和耐受性，并选择能够在成人中达到与多替拉韦 50 毫克每日一次剂量相似的暴露量的剂量。该分析包括针对三个年龄组的每个阶段分两个阶段接受建议剂量的多替拉韦分散片治疗的参与者。该试验已在 ClinicalTrials.gov (NCT01302847) 上注册并正在进行中。

发现

2011年4月20日至2020年2月19日期间，我们招募了181名参与者；其中 96 人服用了多替拉韦分散片。该分析包括 73 名（35 名，48% 女性）参与者，他们接受了最终建议的剂量，中位（范围）年龄为 1 岁（0·1 至 6·0），体重（最小 - 最大）为 8·5 kg（3 ·7 至 18·5)，血浆 HIV-1 RNA 浓度为 4·2 log ₁₀拷贝/mL（2·1 至 7·0），CD4% 为 24·0%（0·3 至 49·0） ; 64 名（87·7%）有治疗经历。每个年龄组（≥2 岁至 <6 岁、≥6 个月至 <2 岁和≥4 周至 <6 个月）内选定的剂量达到了 688、1179 和 1446 的几何平均谷值 (ng/mL) 、24小时曲线下面积(h·mg/L)分别为53、74和65。没有 3 级或更严重的不良事件归因于多替拉韦。