ICMR-National Institute for Research in Tuberculosis (NIRT), Chennai, India.
Groups of TB Hospitals (GTBH), Mumbai, India.
Ther Drug Monit. 2023 Dec 1;45(6):754-759. doi: 10.1097/FTD.0000000000001111. Epub 2023 Jun 5.
Pharmacokinetic (PK) studies are critical for dose optimization, and there is a paucity of linezolid (LZD) PK data for prolonged use in drug-resistant tuberculosis (DR-TB). Therefore, the authors evaluated the pharmacokinetics of LZD at two-time intervals in DR-TB during long-term use.
PK evaluation of LZD was performed at the end of the 8th and 16th weeks of treatment in a randomly selected subset of adult pre-extensively drug-resistant pulmonary tuberculosis patients (n = 18) from a multicentric interventional study (Building Evidence to Advance Treatment of TB/BEAT study; CTRI/2019/01/017310), wherein a daily dose of 600 mg LZD was used for 24 weeks. Plasma LZD levels were measured using a validated high-pressure liquid chromatography (HPLC) method.
The LZD median plasma C max was comparable between the 8th and 16th weeks [18.3 mg/L, interquartile range (IQR: 15.5-20.8 and 18.8 mg/L, IQR: 16.0-22.7, respectively)]. However, the trough concentration increased significantly in the 16th week (3.16 mg/L, IQR: 2.30-4.76), compared with the 8th week (1.98 mg/L, IQR: 0.93-2.75). Furthermore, compared with the 8th week, in the 16th week, there was a significant increase in drug exposure (AUC 0-24 = 184.2 mgh/L, IQR: 156.4-215.8 versus 233.2 mgh/L, IQR: 187.9-277.2), which corroborated with a longer elimination half-life (6.94 hours, IQR: 5.55-7.99 versus 8.47 hours, IQR:7.36-11.35) and decreased clearance (2.91 L/h, IQR: 2.45-3.33 versus 2.19 L/h, IQR: 1.49-2.78).
Long-term daily intake of 600 mg LZD resulted in a significant elevation in trough concentration (>2.0 mg/L) in 83% of the study participants. Furthermore, increased LZD drug exposure may be partly because of decreased clearance and elimination. Overall, the PK data underscore the need for dose adjustment when LZDs are intended for long-term treatment.
药代动力学（PK）研究对于剂量优化至关重要，而对于耐药结核病（DR-TB）的长期使用，利奈唑胺（LZD）的 PK 数据很少。因此，作者在长期使用 LZD 治疗 DR-TB 的两个时间点评估了 LZD 的药代动力学。
在一项多中心干预研究（Building Evidence to Advance Treatment of TB/BEAT 研究；CTRI/2019/01/017310）中，从随机选择的成年广泛耐药性肺结核患者（n=18）中选择一个亚组，在治疗的第 8 周和第 16 周结束时进行 LZD 的 PK 评估，其中使用 600 mg LZD 的每日剂量治疗 24 周。使用经过验证的高效液相色谱（HPLC）法测量 LZD 的血浆水平。
第 8 周和第 16 周的 LZD 中位血浆 Cmax 相似[18.3 mg/L，四分位距（IQR：15.5-20.8 和 18.8 mg/L，IQR：16.0-22.7]。然而，第 16 周的谷浓度显着升高（3.16 mg/L，IQR：2.30-4.76），与第 8 周相比（1.98 mg/L，IQR：0.93-2.75）。此外，与第 8 周相比，第 16 周的药物暴露量（AUC0-24=184.2 mgh/L，IQR：156.4-215.8 与 233.2 mgh/L，IQR：187.9-277.2）显着增加，这与更长的消除半衰期（6.94 小时，IQR：5.55-7.99 与 8.47 小时，IQR：7.36-11.35）和清除率降低（2.91 L/h，IQR：2.45-3.33 与 2.19 L/h，IQR：1.49-2.78）相符。
长期每日摄入 600 mg LZD 导致 83%的研究参与者谷浓度（>2.0 mg/L）显着升高。此外，LZD 药物暴露量增加可能部分是由于清除率和消除率降低所致。总体而言，PK 数据强调了在 LZDs 用于长期治疗时需要调整剂量。
