Department of Pharmacy, College of Pharmacy, Chungnam National Universitygrid.254230.2, Daejeon, Republic of Korea.
Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0189321. doi: 10.1128/aac.01893-21. Epub 2022 Aug 8.
Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight <50 kg and 750 mg/day for weight >50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values <0.4 μg/mL in 1.0-log kill target. However, a fixed dose of 750 mg/day was the only regimen that achieved the target resistance suppression of ≥90% for MIC values of <0.2 μg/mL. In conclusion, fixed-dose prothionamide (750 mg/day), regardless of weight-band, was appropriate for adult MDR-TB patients with weights of 40 to 67 kg.
丙硫异烟胺是一种二线药物，用于治疗耐多药结核病（MDR-TB），已经使用了几十年。然而，其药代动力学（PK）特征仍不清楚。本研究旨在建立丙硫异烟胺的群体 PK 模型，然后应用该模型确定 MDR-TB 患者的最佳给药方案。从在 2 家不同研究医院接受丙硫异烟胺治疗的 27 例 MDR-TB 患者中采集了多个血浆样本。丙硫异烟胺的给药剂量根据世界卫生组织推荐的体重分组剂量方案（体重 <50kg 时 500mg/天，体重 >50kg 时 750mg/天）。采用非线性混合效应模型建立群体 PK 模型。基于系统暴露和 MIC 的目标达标概率被用作响应目标。模拟固定剂量方案（500 或 750mg/天）以比较各种给药方案的疗效。PK 特征充分描述了具有一级消除的两室模型和具有比例缩放的转运吸收室模型。对于 MIC 值 <0.4μg/mL 的所有剂量方案，1.0-log 杀灭目标的有效性均>90%。然而，只有 750mg/天的固定剂量方案对于 MIC 值<0.2μg/mL 的目标耐药抑制率达到≥90%。总之，对于体重为 40 至 67kg 的成年 MDR-TB 患者，无论体重分组如何，固定剂量丙硫异烟胺（750mg/天）均是合适的。
