Background Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure–response relationships in RR/MDR-TB patients. Methods We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18–65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10–15 mg/kg/day) for 9–11 months. Intensive pharmacokinetic sampling was performed after ≥2 weeks of treatment. Total plasma drug exposure (AUC0–24) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC0–24/MIC ratio of 85 and Cmax/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. Results We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC0–24 and Cmax were 35.4 h·mg/L and 8.5 mg/L, respectively. Lower AUC0–24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC0–24/MIC (n = 6/26) and Cmax/MIC (n = 5/26). Lower isoniazid AUC0–24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04–0.89)]. Conclusions Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

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印度尼西亚大剂量异烟肼治疗利福平或多药耐药结核病的药代动力学和药效学

背景 大剂量异烟肼治疗利福平/耐多药结核病（RR/MDR-TB）的药代动力学数据有限。我们的目的是描述高剂量异烟肼的药代动力学，估计暴露目标的实现情况，确定暴露的预测因素，并探索 RR/MDR-TB 患者的暴露-反应关系。方法 我们对 18-65 岁印度尼西亚成年人进行了一项观察性药代动力学研究，并进行了探索性药代动力学/药效学分析，他们接受了包含高剂量异烟肼（10-15 mg/kg/天）的标准化方案治疗肺 RR/MDR-TB。 9-11 个月。治疗≥2周后进行密集药代动力学采样。使用非房室分析评估总血浆药物暴露（AUC0-24）和峰浓度（Cmax）。使用 AUC0-24/MIC 比率 85 和 Cmax/MIC 比率 17.5 作为暴露目标。多变量线性和逻辑回归分析分别用于确定药物暴露和反应的预测因子。结果 我们连续入组了 40 名患者（中位年龄 37.5 岁）。异烟肼的几何平均AUC0-24和Cmax分别为35.4 h·mg/L和8.5 mg/L。较低的 AUC0-24 和 Cmax 值与非慢速乙酰化表型相关（P < 0.05），较低的 Cmax 值与男性相关。在有 MIC 数据的 26 名患者中，不到 25% 的患者达到了异烟肼 AUC0-24/MIC (n = 6/26) 和 Cmax/MIC (n = 5/26) 的建议目标。较低的异烟肼 AUC0-24 值与痰培养转化延迟（治疗 2 个月以上）相关[调整后 OR 0.18 (95% CI 0.04-0.89)]。结论 在大多数患者中观察到异烟肼暴露低于目标，某些低异烟肼暴露的风险群体可能需要调整剂量。低异烟肼暴露对延迟培养物转化的影响值得关注。