IF 12.8 1区 医学 Q1 IMMUNOLOGY Lancet Hiv Pub Date : 2025-02-26 DOI:10.1016/S2352-3018(24)00312-6
Anushka Naidoo, Hylke Waalewijn, Kogieleum Naidoo, Marothi Letsoalo, Gabriela Cromhout, Leora Sewnarain, Nozibusiso R Mosia, Emmanuella C Osuala, Lubbe Wiesner, Roeland E Wasmann, Paolo Denti, Kelly E Dooley, Moherndran Archary
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引用次数: 0

摘要

背景:有关多罗替拉韦在儿童艾滋病和结核病患者中的安全性和药代动力学的数据很少。我们旨在确定接受利福平治疗的儿童每日两次服用 50 毫克多罗替拉韦的药代动力学和安全性,并预测每日一次服用多罗替拉韦与利福平的暴露情况:ORCHID是一项开放标签、连续性、前瞻性队列研究,研究对象为所有具有可评估药代动力学数据的参与者(药代动力学人群),评估多罗替拉韦薄膜衣片50毫克、每天两次、服用利福平和不服用利福平的儿童的药代动力学参数(即吸收率常数、分布容积和口服清除率)(谷值)、最大浓度(Cmax)和服药至服药后24小时的浓度-时间曲线下面积(AUC0-24)。次要结果包括在药代动力学人群中模拟的与利福平合用的每日一次多鲁特韦给药方案的药代动力学参数。本研究已在 ClinicalTrials.gov 注册,编号为 NCT04746547:2021年8月19日至2023年8月17日期间,我们招募并随访了13名儿童,中位体重23-8公斤(IQR 21-7-24-8),中位年龄10岁(5-9-13-0)。其中 7 人为男性,6 人为女性,13 人为黑人。典型的多鲁曲韦清除率为 0-584 L/h(95% CI 0-492-0-724),使用利福平后清除率增加 99-1%(73-2-120)。每日两次服用多鲁曲韦联合利福平的患者的中位Ctrough为1-45 mg/L(变异系数为68%),每日一次服用多鲁曲韦联合利福平的患者的中位Ctrough为1-24 mg/L(变异系数为70%)。基线病毒载量和 CD4 细胞计数的中位数分别为每毫升 2-48 log10 拷贝(IQR 1-64-4-99)和每微升 109 个细胞(77-385)。在第 24 周时,所有 13 名儿童的病毒载量均低于每毫升 50 个拷贝,在第 48 周时,有 12 名儿童的病毒载量低于每毫升 50 个拷贝。报告了四例3级不良事件、无4级不良事件和一例与研究药物无关的严重不良事件(即住院),无因不良事件导致的治疗中断或转换。如果多鲁曲韦50毫克每日一次与利福平合用,儿童的模拟Ctrough值与成人相似,低于目标值(0-064毫克/升)的时间同样很短;90%的成人和儿童高于目标值或低于目标值的时间少于2小时:在体重为20-35公斤的儿童中,每日两次使用多鲁曲韦与利福平可达到治疗浓度,且耐受性良好,病毒抑制率高。模拟结果表明,应在临床研究中对体重为20-35公斤的儿童在合用利福平期间每日一次服用多罗替拉韦的情况进行调查:经费来源:美国国立卫生研究院和南非医学研究委员会。
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Pharmacokinetics and safety of dolutegravir in children receiving rifampicin tuberculosis treatment in South Africa (ORCHID): a prospective cohort study.

Background: Data on the safety and pharmacokinetics of dolutegravir in children with HIV and tuberculosis are scarce. We aimed to determine the pharmacokinetics and safety of dolutegravir 50 mg twice daily in children receiving rifampicin, and to predict exposures for once-daily dolutegravir with rifampicin.

Methods: ORCHID is an open-label, sequential, prospective cohort study in children (<18 years) weighing 20-35 kg initiated on a rifampicin-based tuberculosis regimen and dolutegravir in Durban, South Africa. We collected seven plasma samples over one dosing interval from each patient while on dolutegravir 50 mg twice daily during tuberculosis treatment and while on dolutegravir 50 mg once daily after tuberculosis treatment discontinuation. Pharmacokinetic data were analysed using population modelling in NONMEM version 7.5. The final model was used to perform Monte Carlo simulations in silico of once-daily dolutegravir dosing and time below target concentration (0·064 mg/L). Participants underwent regular clinical and safety visits. HIV viral load was measured at weeks 8, 12, 24, and 48. Primary outcomes were trough concentration (Ctrough), maximum concentration (Cmax), and area under the concentration-time curve from dose to 24 h after dose (AUC0-24) and population plasma pharmacokinetic parameters (ie, absorption rate constant, volume of distribution, and oral clearance) of dolutegravir film-coated tablet 50 mg twice daily in children with and without rifampicin, assessed in all participants with evaluable pharmacokinetic data (pharmacokinetic population). Secondary outcomes included pharmacokinetic parameters for the once-daily dolutegravir dosing option with rifampicin, simulated in the pharmacokinetic population. This study is registered at ClinicalTrials.gov, NCT04746547.

Findings: Between Aug 19, 2021, and Aug 17, 2023, we enrolled and followed up 13 children, with a median weight of 23·8 kg (IQR 21·7-24·8) and median age 10 years (range 5·9-13·0). Seven were male, six female, and 13 Black. Typical dolutegravir clearance was 0·584 L/h (95% CI 0·492-0·724), with an increase in clearance of 99·1% (73·2-120) with rifampicin. Median Ctrough was 1·45 mg/L (coefficient of variation 68%) for participants on twice-daily dolutegravir with rifampicin and 1·24 mg/L (70%) for participants on once-daily dolutegravir without rifampicin. Median viral load and CD4 count at baseline were 2·48 log10 copies per mL (IQR 1·64-4·99) and 109 cells per μL (77-385), respectively. Viral load was less than 50 copies per mL in all 13 children completing week 24 and in 12 children at week 48. Four grade 3 adverse events, no grade 4 adverse events, and one serious adverse event (ie, hospitalisation) unrelated to study drug were reported, with no treatment discontinuations or switches due to adverse events. Simulated Ctrough values for dolutegravir 50 mg once daily if it were co-administered with rifampicin in children were similar to those reported in adults, with time below the target (0·064 mg/L) similarly short; 90% of adults and children either above the target or below the target for less than 2 h.

Interpretation: Twice-daily dolutegravir with rifampicin in children weighing 20-35 kg achieved therapeutic concentrations and was well tolerated with high rates of viral suppression. Simulations suggest that once-daily dolutegravir during rifampicin co-administration in children weighing 20-35 kg should be investigated in clinical studies.

Funding: National Institutes of Health and South African Medical Research Council.

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来源期刊
Lancet Hiv
Lancet Hiv IMMUNOLOGYINFECTIOUS DISEASES&-INFECTIOUS DISEASES
CiteScore
19.90
自引率
4.30%
发文量
368
期刊介绍: The Lancet HIV is an internationally trusted source of clinical, public health, and global health knowledge with an Impact Factor of 16.1. It is dedicated to publishing original research, evidence-based reviews, and insightful features that advocate for change in or illuminates HIV clinical practice. The journal aims to provide a holistic view of the pandemic, covering clinical, epidemiological, and operational disciplines. It publishes content on innovative treatments and the biological research behind them, novel methods of service delivery, and new approaches to confronting HIV/AIDS worldwide. The Lancet HIV publishes various types of content including articles, reviews, comments, correspondences, and viewpoints. It also publishes series that aim to shape and drive positive change in clinical practice and health policy in areas of need in HIV. The journal is indexed by several abstracting and indexing services, including Crossref, Embase, Essential Science Indicators, MEDLINE, PubMed, SCIE and Scopus.
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