Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA.
Clin Infect Dis. 2023 May 3;76(9):1658-1670fc. doi: 10.1093/cid/ciac973.
Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures.
Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222).
Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations.
There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.
儿童和青少年初治结核病一线药物的最佳剂量仍不确定。我们旨在确定使用世界卫生组织推荐剂量或更高剂量的一线药物治疗的儿童是否能获得良好的结局和足够的药代动力学（PK）暴露。
筛选标题、摘要和全文文章。我们从 2010 年至 2021 年检索了 PubMed、EMBASE、CENTRAL 和试验登记处。我们纳入了年龄<18 岁的正在接受利福平（RIF）、吡嗪酰胺、异烟肼和乙胺丁醇治疗的药物敏感结核病儿童的研究。结局为治疗成功率和药物暴露。系统评价的方案已在 PROSPERO（注册号：CRD42021274222）预先注册。
在确定的 304 项研究中，有 46 项符合全文审查标准，12 项和 18 项研究分别纳入了疗效和 PK 分析。在纳入的 1830 名儿童中，有 82%（范围：25%-95%）的结局良好。在世界卫生组织推荐剂量下，RIF、吡嗪酰胺和乙胺丁醇在儿童中的暴露量低于成人。6 岁及以下儿童的 AUC 比年长儿童低 35%（平均值为 14.4[95%CI 9.9-18.8]比 22.0[13.8-30.1]μg·h/mL），HIV 阳性儿童的 RIF AUC 比 HIV 阴性儿童低 35%（17.3[11.4-23.2]比 26.5[21.3-31.7]μg·h/mL）。异质性和小样本量是主要的局限性。
结局差异较大，平均有 82%的结局良好。儿童的药物暴露量低于成人。年龄较小的儿童和/或 HIV 阳性儿童对 RIF 的暴露不足。需要标准化 PK 儿科研究和个体患者数据分析，并进行安全性评估，以确定最佳剂量。
