Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis.
Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis.
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南非利福平耐药结核病患者血浆和细胞内贝达喹啉及其代谢产物M2浓度之间的关系
DOI：
10.1128/aac.02399-20
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发表时间：
2021-10-18
影响因子：
4.9
通讯作者：
Wiesner L
中科院分区：
文献类型：
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作者：
Ngwalero P;Brust JCM;van Beek SW;Wasserman S;Maartens G;Meintjes G;Joubert A;Norman J;Castel S;Gandhi NR;Denti P;McIlleron H;Svensson EM;Wiesner L
推荐贝达喹啉用于治疗所有利福平耐药结核病（RR-TB）患者。贝达喹啉在细胞内蓄积，但其细胞内药代动力学尚未表征，这可能对剂量优化有影响。我们开发了一种新的检测方法，使用高效液相色谱-串联质谱（LC-MS/MS）来测量南非RR-TB患者中贝达喹啉及其主要代谢产物M2的细胞内浓度。21名参与者入组，并在治疗第1、2和6个月以及贝达喹啉治疗完成后3和6个月进行血浆和外周血单核细胞（PBMC）稀疏采样。在第2个月进行密集采样。我们使用非房室分析来描述血浆和细胞内暴露，并使用群体药代动力学模型来探讨血浆和细胞内药代动力学之间的关系以及关键协变量的影响。治疗第1个月至第6个月期间，血浆中贝达喹啉浓度范围为94.7 - 2，540 ng/ml，PBMC中贝达喹啉浓度范围为16.2 - 5，478 ng/ml，6个月治疗期间，血浆中M2浓度范围为34.3 - 496 ng/ml，PBMC中M2浓度范围为109.2 - 16，764 ng/ml。贝达喹啉的血浆浓度高于M2，但M2的细胞内浓度显著高于贝达喹啉。在药代动力学建模中，我们估计贝达喹啉和M2的细胞内血浆蓄积比呈线性增加，治疗2个月后达到最大效应。贝达喹啉治疗开始后1个月和2个月的典型细胞内-血浆比值分别为0.61（95%置信区间[CI]：0.42 - 0.92）和1.10（95% CI：0.74 - 1.63），M2为12.4（95% CI：8.8 - 17.8）和22.2（95% CI：15.6 - 32.3）。与HIV阴性患者相比，HIV阳性患者中贝达喹啉和M2的细胞内-血浆比值降低了54%（95% CI：24 - 72%）。治疗停止后6个月，在PBMC中可检测到贝达喹啉和M2。M2在细胞内的蓄积浓度高于贝达喹啉，支持M2是磷脂质病主要诱导剂的体外证据。
Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.