Desmond Tutu TB Centre, Department of Paediatrics, Stellenbosch University, Cape Town, South Africa.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Int J Tuberc Lung Dis. 2021 Nov 1;25(11):896-902. doi: 10.5588/ijtld.20.0870.
High-dose isoniazid (INH) (15-20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse. This observational study included South African children (<15 years) receiving INH as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC) and maximum concentration (C). AUC and C values were compared against proposed adult targets. Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC was 19.46 µgh/mL (IQR 10.76-50.06) and C was 5.14 µg/mL (IQR 2.69-13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC (geometric mean ratio GMR 0.19, 95% CI 0.15-0.26; < 0.001) and C (GMR 0.20, 95% CI 0.15-0.26; < 0.001). INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.
高剂量异烟肼（INH）（15-20 毫克/千克/天）可用于克服低水平 INH 耐药，但药代动力学数据很少。本观察性研究纳入了南非接受 INH 预防治疗或治疗耐多药结核（MDR-TB）暴露或疾病的儿童（<15 岁）。在给予 20 毫克/千克 INH 剂量后进行药代动力学采样。采用非房室分析和多变量回归模型评估关键协变量与曲线下面积（AUC）和最大浓度（C）的相关性。AUC 和 C 值与成人目标值进行了比较。共纳入 77 例儿童，中位年龄为 3.7 岁；51 例（66%）患有 MDR-TB 疾病，26 例（34%）患有 MDR-TB 暴露。5 例 HIV 阳性，其中 4 例年龄≥5 岁。AUC 中位数为 19.46µgh/mL（IQR 10.76-50.06），C 中位数为 5.14µg/mL（IQR 2.69-13.2）。在<5 岁儿童的多变量分析中，MDR-TB 疾病（与暴露相比）与 AUC 显著降低相关（几何均数比 GMR 0.19，95%CI 0.15-0.26；<0.001）和 C（GMR 0.20，95%CI 0.15-0.26；<0.001）。患有 MDR-TB 疾病的儿童的 INH 浓度远低于预期，但与之前报道的患有 MDR-TB 暴露的儿童相似。进一步的研究应证实这些发现并探讨可能的原因。
