Efficacy of isoniazid in paediatric tuberculosis: an individual participant data meta-analysis.

Our aim was to determine the association between isoniazid exposure and clinical outcomes, to develop a pharmacokinetic model, and to optimise the dosing regimen in children treated for drug-susceptible (DS)-TB.

我们的目标是确定异烟肼暴露与临床结果之间的关联，开发药代动力学模型，并优化治疗药物敏感性（DS）-TB儿童的剂量方案。

Methods

For this individual participant data meta-analysis, PubMed was searched for observational studies, involving children (aged 0-18 years), being treated for DS-TB.

在这项个体患者数据的荟萃分析中，通过PubMed检索涉及儿童（0-18岁）接受治疗的DS-TB的观察性研究。

The relationship between isoniazid exposure and clinical outcomes was analysed using a mixed effects logistic regression model.

使用混合效应逻辑回归模型分析异烟肼暴露与临床结果之间的关系。

Pharmacokinetic parameters were described using non-linear mixed effects modelling.

药代动力学参数使用非线性混合效应模型进行描述。

The pharmacokinetic target was the median adult area under the concentration-time curve at steady-state (AUCss) of 23.4 mg·h·L-1.

药代动力学目标是中位成人稳态时药物浓度-时间曲线下面积（AUCss）的中位数，目标值为23.4 mg·h·L-1。

Results

Six studies provided clinical outcomes, including 405 patients, of which 21% had unfavourable outcomes. 16 studies (1255 patients) were included in the pharmacokinetic model.

六项研究提供了临床结果，包括405名患者，其中21%的患者预后不良。16项研究（1255名患者）被纳入药代动力学模型。

Unfavourable outcomes were only related to lower body mass index (BMI) for age z-score (BAZ) (OR 0.96, 95% CI 0.93-0.99; p<0.05).

预后不良仅与较低的身体质量指数（BMI）年龄z分数（BAZ）相关（OR 0.96，95% 置信区间 0.93-0.99；p<0.05）。

Isoniazid exposure was impacted by N-acetyltransferase 2 (NAT2) genotype, weight, age and nutritional status (using BAZ).

异烟肼的暴露受到N-乙酰转移酶2（NAT2）基因型、体重、年龄和营养状况（使用BAZ评估）的影响。

With currently recommended World Health Organization (WHO) doses, isoniazid exposure was similar to that of adults.

在目前推荐的世界卫生组织（WHO）剂量下，异烟肼的暴露与成人相似。

Pharmacokinetic target attainment was 71.7% and 29.5% for slow and fast metabolisers, respectively (p<0.05); 50.5% for patients with BAZ >0 and 42.6% for malnourished patients (BAZ < -2) (p<0.05).

药代动力学目标达成率对于慢代谢者和快代谢者分别为71.7%和29.5%（p<0.05）；对于BAZ>0的患者为50.5%，而对于营养不良患者（BAZ<-2）为42.6%（p<0.05）。

The model-informed dosing regimen showed that fast metabolisers could benefit from higher isoniazid dosing, especially in malnourished children.

基于模型的剂量方案表明，快代谢者尤其是营养不良的儿童，可以从更高的异烟肼剂量中获益。

Conclusions

Our findings showed that the only predictor of unfavourable clinical outcomes was a lower BAZ.

我们的研究发现，唯一预测不良临床结果的因素是较低的体脂指数（BAZ）。

We support the current WHO-recommended dosing regimen for isoniazid.

我们支持目前世界卫生组织推荐的异烟肼剂量方案。

To equalise and attain our pharmacological target for all children, dosing regimens could be adjusted on NAT2 genotype and nutritional status.

为了使所有儿童达到我们的药物治疗目标，可以基于NAT2基因型和营养状况调整剂量方案。