Application, methods, and practice of therapeutic drug monitoring in individualized anti-tuberculosis therapy

doi:10.19982/j.issn.1000-6621.20260144

Abstract

Abstract:

Tuberculosis remains one of the leading causes of death from infectious diseases globally. In anti-tuberculosis treatment, the pharmacokinetic and pharmacodynamic properties of drugs are crucial for optimizing therapeutic efficacy, avoiding treatment delays, acquired drug resistance, and adverse drug reactions. Therapeutic drug monitoring (TDM) provides a basis for formulating precise dosing regimens by measuring drug concentrations in patients, combining quantitative pharmacokinetic models with therapeutic windows, thereby enhancing treatment success rates and controlling toxicity risks. In recent years, with the deepening of population pharmacokinetic and pharmacodynamic research, therapeutic monitoring strategies for first-line and second-line anti-tuberculosis drugs have been increasingly refined. This article systematically reviews the detection methods, main clinical application scenarios, and monitoring schemes and target concentrations of anti-tuberculosis drugs in TDM. On this basis, it focuses on updating the latest research progress and monitoring recommendations for pregnant women and children. Combining clinical practice and research progress in China, it discusses their role and value in optimizing tuberculosis treatment, especially in individualized dosing.

Key words: Antitubercular agents, Drug monitoring, Pharmacokinetics, Clinical protocols, Review

CLC Number:

Cheng Wen, Guo Lifang, Nie Wenjuan. Application, methods, and practice of therapeutic drug monitoring in individualized anti-tuberculosis therapy[J]. Chinese Journal of Antituberculosis, 2026, 48(6): 882-891. doi: 10.19982/j.issn.1000-6621.20260144

Figures/Tables 2

药物	安全性特征	孕期和(或)产后的药代动力学变化	TDM建议	TDM分级
一线抗结核药物
异烟肼	周围神经病变(可使用维生素B6预防)、肝毒性、皮疹	清除率较产后增加约26%;孕晚期AUC_0-24h较产后降低25%,C_max降低23%	建议根据NAT2基因型指导剂量。慢代谢者标准剂量可能已足够;快代谢者可能需要增加剂量或缩短给药间隔。推荐TDM	P1
利福平	肝毒性、胃肠道反应、橙色体液(无害)、强效细胞色素酶诱导剂	孕期与产后AUC_0-24h和C_max无明显差异	通常无需常规TDM,但与其他药物(如抗HIV药物)合用时需监测疗效和药物相互作用	P3
利福喷丁	与利福平类似,半衰期更长	HIV阴性孕妇:孕期清除率较产后低28%,AUC升高;HIV阳性孕妇(服用依非韦伦):清除率比HIV阴性孕妇高30%,孕期与产后无明显差异	标准剂量无需调整,但HIV阳性孕妇(服用依非韦伦)可能需要关注。TDM仅用于特殊人群	P2
吡嗪酰胺	肝毒性、高尿酸血症、关节痛	清除率较产后增加13%;AUC与产后无明显差异。总体受妊娠影响最小	通常无需常规TDM,但治疗反应不佳时可考虑	P3
乙胺丁醇	视神经炎(剂量-时间依赖性)、高尿酸血症	清除率较产后增加50%;孕晚期AUC_0-24h较产后降低39%,C_max降低23%	因妊娠期肾清除率明显增加,建议TDM以指导剂量调整(可能需要增加剂量)	P1
耐药A组药物
左氧氟沙星	耐受性良好。常见不良反应:腹泻、恶心、腹胀、关节痛、轻度QTc间期延长	妊娠使左氧氟沙星清除率平均增加38.1%(95%CI:23.4%~57.1%),药物暴露量明显低于非妊娠人群。与产后相比,孕中期的AUC_0-12h较低。但总体暴露量仍在既往报道的参考范围内	妊娠期左氧氟沙星清除率明显增加,可能导致药物暴露水平下降。建议在治疗反应不佳或怀疑药物暴露不足时进行TDM,以指导可能的剂量调整	P2
莫西沙星	明显QTc间期延长(10~20ms)、头痛、头晕等	第二孕期AUC_0-24h为31.6,第三孕期AUC_0-24h为32.0,产后18周暴露量为34.9mg·h·L^-1。均在非孕期参考范围内	孕期数据极少,但因QTc风险和治疗窗窄,建议TDM	P2
贝达喹啉	恶心、关节痛、头痛、QTc间期延长(10~15ms,峰值在第15周)	第三孕期C_max中位数为1.69(0.30~2.93)mg/L,总体产前暴露低于预期	孕期暴露低于预期,建议TDM以优化剂量。尚无明确剂量调整方案	P1
利奈唑胺	耐受性差,毒性风险高。主要不良反应包括:骨髓抑制(贫血、血小板、白细胞减少)、周围神经病变、视神经病变	在孕晚期和产后,利奈唑胺的药物暴露量明显升高。一项个案报告中,第二孕期AUC_0-24h为48,第三孕期AUC_0-24h为106,产后暴露量为203mg·h·L^-1。产后暴露升高4倍,导致多发性神经病变停药	强烈推荐TDM,因毒性风险与暴露量相关,且孕期暴露变化大	P1
耐药B组药物
氯法齐明	耐受性良好。主要不良反应:皮肤及体液变色、皮肤干燥瘙痒、QTc间期延长	母乳中浓度高于母体血浆,与产后相比,氯法齐明在妊娠晚期的暴露量明显增高	鉴于缺乏孕期暴露水平与临床结局的相关性数据,且其长半衰期限制了TDM的常规应用,目前不推荐常规TDM	P2
环丝氨酸/特立齐酮	神经精神毒性(抑郁、精神病、癫痫)	未查到孕期药代动力学数值。产后可能更易发生神经精神不良事件。母乳中浓度约为母体的20%,婴儿暴露量低	推荐TDM以将浓度控制在治疗窗(20~35mg/L)内,避免神经毒性	P1
耐药C组药物+其他
德拉马尼	成人耐受性良好	妊娠对德拉马尼及其主要代谢物的药代动力学无明显影响	基于现有证据,妊娠对德拉马尼的暴露量无明显影响,因此,不推荐因妊娠而常规进行TDM	P3
阿米卡星	耳毒性、肾毒性(耐受性差)	不推荐孕期使用(有先天性耳聋风险)	不推荐孕期使用,故无TDM建议	P0
乙硫异烟胺/丙硫异烟胺	胃肠道反应、甲状腺功能减退、致畸可能	不推荐孕期使用	不推荐孕期使用	P0
美罗培南/亚胺培南	耐受性差	无数据	无孕期数据,通常不用于结核病的常规治疗	P3
对氨基水杨酸	耐受性差	无数据	无孕期数据	P3
高剂量异烟肼	同异烟肼,但肝毒性风险增加	未查到具体孕期药代动力学数值(标准剂量数据见一线抗结核药物)	建议TDM,参考异烟肼	P1
普托马尼	耐受性良好	无数据	无孕期数据	P3

药物	药代动力学变化特征	TDM建议	TDM监测分级
异烟肼	典型口服清除率:慢乙酰化型为4.44L/h,中间型为11.6L/h,快乙酰化型为14.6L/h。世界卫生组织推荐剂量(10mg·kg^-1·d^-1)在<2岁儿童可达成人目标浓度;3月龄以下婴儿消除受损,需个体化剂量	建议根据NAT2基因型和治疗反应进行监测;需注意监测小月龄婴儿	P2
利福平	儿童清除率高于成人,<5岁儿童尤为明显。婴儿C_max仅为2.9μg/ml,远低于成人目标(8~24μg/ml)。2岁儿童典型口服清除率约为8.15L/h	现有剂量(世界卫生组织推荐10~15mg·kg^-1·d^-1)在多数儿童中无法达到成人目标C_max(<8μg/ml)	P1
吡嗪酰胺	2岁儿童按修订世界卫生组织剂量(35mg·kg^-1·d^-1)给药后C_max为47.11μg/ml,AUC为175.2μg·h·ml^-1。HIV感染儿童C_max降低约15%,AUC降低约21%。<4岁儿童体质量校正后清除率更高,总暴露量较年长儿低16%	在<2岁幼儿中可考虑监测以确保治疗浓度	P3
乙胺丁醇	10kg儿童清除率为15.9L/h;在合用洛匹那韦/利托那韦的HIV感染儿童中,生物利用度降低32%。新生儿期生物利用度仅为大龄儿童的73%。世界卫生组织推荐剂量(15~25mg·kg^-1·d^-1)下,多数儿童C_max[中位数(四分位数)为1.20(0.85~1.68)mg/L]低于成人目标范围(2~6mg/L)	鉴于现有剂量下暴露量普遍不足,建议在治疗反应不佳或存在耐药风险者中加强监测	P2
链霉素	儿童中的药代动力学数据有限,主要从成人数据外推。主要经肾小球滤过排泄,肾功能不全者清除率明显降低。儿童C_max目标为35~45μg/ml	需监测血药浓度以平衡疗效与毒性风险,尤其是有残余肾功能或合并使用其他肾毒性/耳毒性药物者	P2
利奈唑胺	儿童按10mg·kg^-1·d^-1给药后,中位AUC_0-24h 201mg·h·L^-1,显著高于成人600mg/d剂量的暴露量AUC_0-24h<150mg·h·L^-1	强烈建议进行TDM;初始给药后建议监测稳态谷浓度;临床出现骨髓抑制或神经毒性时亦应监测	P1
莫西沙星	年龄/体质量差异:世界卫生组织推荐剂量下,>10kg儿童药物暴露与成人相似;<10kg(尤其低龄)儿童存在明显暴露不足,需比当前推荐剂量提高33%~56%方可达到成人暴露目标	体质量<10kg的低龄患儿建议监测;出现QTc间期延长或合并其他导致QT间期延长药物时加强监测	P2
左氧氟沙星	分散片生物利用度比非分散片高出29%。清除率受年龄影响,出生时达50%,8个月龄达90%。世界卫生组织推荐剂量(15~20mg·kg^-1·d^-1)在<24kg或<10岁患儿中的暴露量仅为成人目标的50%	<24kg或<10岁患儿强烈建议TDM;使用高剂量(>20mg·kg^-1·d^-1)时建议监测;出现QTc间期延长时应加强监测	P2
贝达喹啉	儿童单位体质量清除率比成人高约49%(1.49倍)。合并使用利福平或利福喷丁时清除率分别升高378%和296%。Ⅱ期研究:≥5岁患儿使用成人剂量或半量(依年龄/体质量)12周后,AUC_0-168为119000ng·h·ml^-1(12~<18岁)和118000ng·h·ml^-1(5~<12岁),均在成人目标AUC范围内	合并使用利福霉素类(利福平/利福喷丁)时必须TDM(药物相互作用致清除率大幅升高);体质量极端值或低白蛋白血症患儿建议监测;无明确危险因素时一般无需常规TDM	P2(无合并用药/风险因素时)→P1(合并利福霉素类药物时强制监测)
氯法齐明	儿童中位wAUC为162.94mg·h·L^-1,较成人RR-TB患者目标111.79mg·h·L^-1高出25%以上	所有儿童必须TDM(暴露明显高于成人目标)。模型模拟建议(尚未写入指南):体质量5~14kg:50mg,每2天1次;体质量≥15kg:50mg,1次/d	P1
特立齐酮/环丝氨酸	体质量13kg儿童清除率0.474L/h。清除率随年龄增长成熟。胶囊拆开粉剂给药吸收速度明显快于整粒吞服(10.1min和72.6min),生物利用度无影响。体质量评分低于-2者生物利用度降低16%。2022年世界卫生组织推荐儿童剂量在3~10kg及36~46kg体质量组暴露低于成人500mg日剂量目标	世界卫生组织指出儿童剂量在多个体质量组暴露不足,建议加强TDM以优化剂量	P2→P1(肾功能不全/神经毒性时强制监测)
乙硫异烟胺	标准体质量儿童清除率为8.88L/h,分布容积为21.4L。儿童剂量约20mg·kg^-1·d^-1(10.4~25.3mg/kg)时,多数患儿C_max可>2.5μg/ml目标值。0~2岁婴幼儿C_max中位数为7.66μg/ml,高于年长儿童	常规管理一般无需常规TDM;但合并HIV感染、合并使用利福平或重症结核病(如结核性脑膜炎)可考虑TDM;出现甲减/肝毒性/严重胃肠道不耐受时建议加强监测	P3
丙硫异烟胺	儿童推荐剂量:10~20mg·kg^-1·d^-1(分次或顿服);或15~20mg/kg(最大1g),1次/d(首选顿服以达到更高峰浓度)	TDM不常规需要。仅特定临床情境(疗效不佳、严重不良反应、药物相互作用)可考虑TDM。丙硫异烟胺治疗窗窄,高剂量时需警惕中枢神经系统毒性和肝毒性	P3
对氨基水杨酸	体质量13kg儿童典型清除率为9.79L/h。依非韦伦合并使用时清除率增高。模拟研究显示仅当使用世界卫生组织推荐较高剂量范围(300mg/kg,1次/d)时才能达到目标暴露	常规管理一般无需常规TDM;使用低剂量或疗效不佳时可考虑TDM;出现甲状腺功能减退症或严重胃肠道不耐受时加强监测。肾功能不全者(主要经肾排泄)建议TDM	P3(一般管理)→P2(肾功能不全/低剂量/甲状腺功能减退症高风险时建议监测)
德拉马尼	年龄分层剂量方案:12~<18岁:100mg。2次/d;6~<12岁:50mg,2次/d;3~<6岁:25mg,2次/d。以上三组儿童的暴露水平与成人100mg,2次/d相当。0~3岁婴儿采用基于体质量的方案(5mg,1次/d至10mg,2次/d)后,实测暴露低于基于年长儿药代动力学模型的预测值,未达到成人目标暴露	0~<3岁婴幼儿建议TDM(暴露普遍低于目标);其他年龄组一般常规管理即可,无明确TDM必要	P3(≥3岁)→P2(0~<3岁婴幼儿建议加强监测)
阿米卡星	传统推荐15mg·kg^-1·d^-1(每8~12h 1次),但TDM引导下20mg/kg 1次/d方案可提高目标达标概率并降低肾/耳毒性风险。目标浓度:C_max值为35~45μg/ml(疗效),C_min值<1~2μg/ml(避免肾/耳毒性)	所有儿童必须TDM(肾毒性和耳毒性风险极高,治疗窗窄)。低体质量患儿更需强化监测。2020年世界卫生组织指南明确建议TDM以优化剂量并减少不良反应	P1
卷曲霉素	儿童药代动力学数据极度缺乏,剂量主要从成人外推	所有儿童必须TDM(肾毒性和耳毒性风险高,治疗窗窄)。肾功能不全者更需强化监测。监测C_max(疗效)和C_min(毒性)	P1

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