Division of Pharmacology and Therapy, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Unit of PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
Arch Dis Child. 2022 Jan;107(1):70-77. doi: 10.1136/archdischild-2020-321426. Epub 2021 Jun 28.
To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).
Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.
Hasan Sadikin Hospital, Bandung, Indonesia.
Individuals aged 0-18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.
Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.
Plasma exposures during the daily dosing interval (AUC), peak plasma concentrations () and CSF concentrations.
Among 20 eligible patients, geometric mean AUC of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC and of all drugs. All patients had suboptimal rifampicin AUC for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2-3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC of isoniazid, rifampicin and pyrazinamide along with of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).
Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.
评估异烟肼、利福平、吡嗪酰胺在结核性脑膜炎（TBM）患儿和青少年患者中的药代动力学和安全性/耐受性。
前瞻性观察性药代动力学研究，探索性药代动力学/药效学分析。
印度尼西亚万隆哈桑·萨迪克医院。
根据世界卫生组织（WHO）修订的推荐治疗指南，接受一线抗结核药物治疗剂量且临床诊断为 TBM 的 0-18 岁个体。
在治疗第 2 天和第 10 天评估异烟肼、利福平、吡嗪酰胺的血浆和脑脊液（CSF）浓度。
每日给药间隔期间的血浆暴露量（AUC）、血浆峰浓度（Cmax）和 CSF 浓度。
在 20 名符合条件的患者中，异烟肼、利福平、吡嗪酰胺的几何平均 AUC 分别为第 2 天的 18.5、66.9 和 315.5 小时·mg/L；第 10 天的 14.5、71.8 和 328.4 小时·mg/L。所有药物的 AUC 和 Cmax 均存在较大的个体间差异。所有患者的利福平 AUC 均低于 TBM 治疗指征的最佳水平，且利福平 CSF 浓度极低。4 名患者在治疗的前 4 周内发生 2-3 级药物性肝损伤（DILI），抗结核药物暂时停用，在重新使用利福平和异烟肼后，未再出现 DILI。与未发生 DILI 的患者相比，发生 DILI 的患者第 10 天的异烟肼、利福平、吡嗪酰胺的 AUC 和异烟肼、吡嗪酰胺的 Cmax 更高（p<0.05）。
强烈需要为 TBM 患儿和青少年患者提供更高剂量的利福平。需要进一步的研究来证实较高的异烟肼、利福平、吡嗪酰胺的血浆浓度与 DILI 发展之间的关系。
