Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China.
The Fifth People's Hospital of Suzhou, Suzhou, China.
Clin Infect Dis. 2021 Nov 2;73(9):e3520-e3528. doi: 10.1093/cid/ciaa1569.
Prospective studies correlating pharmacokinetic/pharmacodynamic (PK/PD) indices to clinical responses are urgently needed. This study aimed to find clinically relevant PK/PD thresholds that can be used for treatment optimization.
Pharmacokinetic sampling and minimum inhibitory concentration (MIC) measurements were performed for patients with culture-confirmed tuberculosis (TB). Classification and regression tree (CART) analysis was applied to obtain PK and/or PD thresholds for first-line drugs predictive of 2-week/month culture conversion, treatment outcome determined at 6-8 months, acute kidney injury (AKI), and drug-induced liver injury (DILI). Least absolute shrinkage and selection operator (LASSO) logistic regression was used for model development and validation.
Finally, 168 and 52 patients with TB were included in development and validation cohorts for analysis, respectively. Area under the concentration-time curve (AUC)/MIC below CART-derived thresholds for pyrazinamide of 8.42, pyrazinamide of 2.79, or rifampicin of 435.45 were the predominant predictors of 2-week culture conversion, 2-month culture conversion, or treatment success, respectively. Isoniazid AUC >21.78 mg · h/L or rifampicin AUC >82.01 mg · h/L were predictive of DILI or AKI during TB treatment. The predictive performance of trained LASSO models in the validation cohort was evaluated by receiver operating characteristic curves and ranged from 0.625 to 0.978.
PK/PD indices and drug exposure of TB drugs were associated with clinical outcome and adverse events. The effect of CART-derived thresholds for individualized dosing on treatment outcome should be studied in a randomized controlled trial.
迫切需要进行将药代动力学/药效学（PK/PD）指标与临床反应相关联的前瞻性研究。本研究旨在寻找可用于优化治疗的临床相关 PK/PD 阈值。
对经培养证实的结核病（TB）患者进行药代动力学采样和最小抑菌浓度（MIC）测量。应用分类回归树（CART）分析获得预测 2 周/月培养转换、6-8 个月治疗结果、急性肾损伤（AKI）和药物性肝损伤（DILI）的一线药物的 PK 和/或 PD 阈值。使用最小绝对收缩和选择算子（LASSO）逻辑回归进行模型开发和验证。
最终，168 例和 52 例 TB 患者分别纳入开发和验证队列进行分析。吡嗪酰胺 AUC/MIC 低于 CART 衍生的 8.42、2.79 或利福平 435.45 阈值与 2 周培养转换、2 个月培养转换或治疗成功的主要预测因素。异烟肼 AUC>21.78 mg·h/L 或利福平 AUC>82.01 mg·h/L 与 TB 治疗期间的 DILI 或 AKI 相关。经训练的 LASSO 模型在验证队列中的预测性能通过接受者操作特征曲线进行评估，范围为 0.625 至 0.978。
TB 药物的 PK/PD 指标和药物暴露与临床结局和不良事件相关。应在随机对照试验中研究 CART 衍生的个体化给药阈值对治疗结果的影响。
