Pharmacokinetics and pharmacodynamics of adult dolutegravir tablets in treatment-experienced children with HIV weighing at least 20 kg.
Pharmacokinetics and pharmacodynamics of adult dolutegravir tablets in treatment-experienced children with HIV weighing at least 20 kg.
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成人多替拉韦片剂在体重至少 20 kg 且经历过治疗的 HIV 儿童中的药代动力学和药效学。
DOI：
10.1097/qad.0000000000003576
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kusi-Amponsah,Isaa
中科院分区：
文献类型：
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作者：
Martyn-Dickens,Charles;Ojewale,Oluwayemisi;Sly-Moore,Eugenia;Dompreh,Albert;Enimil,Anthony;Amissah,AikinsKofi;Bosomtwe,Dennis;FrimpongAppiah,Augustina;Sarfo,AmaD;Opoku,Theresah;Asiedu,Priscilla;Dong,StephenK;Kusi-Amponsah,Isaa
目的：有限的药代动力学/药效学数据是基于多洛替格列韦的抗逆转录病毒疗法(ART)在儿童中推广的障碍。设计：前瞻性、观察性、药动学和安全性研究。方法：研究体重至少20 kg的HIV感染儿童的成人薄膜包衣多洛替格雷50 mg片剂的药代动力学/药效学。方法：选择体重至少20 kg且有病毒载量抑制的儿童作为研究对象，改用基于多洛替格韦的治疗。在服用多洛替格韦至少4周和7个月后，分别在给药后0、1、4、8、12和24小时采集血样。用有效的LC MS/MS测定多洛替格韦的浓度，用非室分析计算药代动力学参数。结果：在25名受试者中，92%的人接受了基于法韦伦兹的抗逆转录病毒治疗，60.0%的人是男性。在两次药代动力学检查中，体重在20公斤至40公斤以下的成人和儿童每日1次服用50 mg多洛替格雷的平均暴露剂量、峰值和谷值均高于参考值，但更接近成人每日2次服用50 mg的平均值。体重从20公斤到不到40公斤的儿童接触多洛替格列韦的几率更高。48周内耐受性良好，病毒学效果良好。结论：本研究人群中较高的多洛替格韦暴露表明，进一步的研究和密切监测应调查多洛替格韦在更多儿童中的长期不良反应。
Objective:Limited pharmacokinetic/pharmacodynamic data are a barrier to the scale-up of dolutegravir-based antiretroviral therapy (ART) in children. We examined the pharmacokinetics/pharmacodynamics of the adult film-coated dolutegravir 50 mg tablets in children with HIV infection weighing at least 20 kg.Design:A prospective, observational, pharmacokinetic, and safety study.Methods:Treatment-experienced children with HIV weighing at least 20 kg and evidence of viral load suppression on ART were enrolled and switched to dolutegravir-based therapy. After at least 4 weeks and 7 months on dolutegravir-based therapy, blood samples were collected at 0, 1, 4, 8, 12, and 24-h postdose. Dolutegravir concentrations were measured using validated LCMS/MS and pharmacokinetic parameters calculated by noncompartmental analysis. Descriptive statistics were used to summarize pharmacokinetic parameters and comparisons with published reference values.Results:Of 25 participants, 92% were on efavirenz-based ART and 60.0% were men. Dolutegravir mean exposure, peak and trough concentrations at both pharmacokinetic visits were higher than the mean reference values in adults and children weighing 20 kg to less than 40 kg treated with 50 mg once daily, but were closer to the mean values in adults given 50 mg twice a day. Children weighing 20 kg to less than 40 kg had even higher dolutegravir exposures. The regimens were well tolerated with good virologic efficacy through week 48.Conclusion:The higher dolutegravir exposure in our study population suggests that further studies and close monitoring should investigate the adverse effects of dolutegravir in more children and in the long term.