Linezolid Pharmacokinetics/Pharmacodynamics-Based Optimal Dosing for Multidrug-Resistant Tuberculosis

Wenqiang Zhou; Wenjuan Nie; Qingfeng Wang; Wenhui Shi; Yang Yang; Qi Li; Hui Zhu; Zhongquan Liu; Yangming Ding; Yu Lu; Naihui Chu

doi:10.1016/j.ijantimicag.2022.106589

Linezolid Pharmacokinetics/Pharmacodynamics-Based Optimal Dosing for Multidrug-Resistant Tuberculosis

Int J Antimicrob Agents. 2022 Jun;59(6):106589. doi: 10.1016/j.ijantimicag.2022.106589. Epub 2022 Apr 9.

Authors

Wenqiang Zhou¹, Wenjuan Nie¹, Qingfeng Wang¹, Wenhui Shi¹, Yang Yang¹, Qi Li¹, Hui Zhu², Zhongquan Liu², Yangming Ding², Yu Lu³, Naihui Chu⁴

Affiliations

¹ Tuberculosis Department, Beijing Chest Hospital, Capital Medical University, Beijing, China.
² Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, and Beijing Chest Hospital, Capital Medical University, Beijing, China.
³ Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, and Beijing Chest Hospital, Capital Medical University, Beijing, China. Electronic address: luyu4876@hotmail.com.
⁴ Tuberculosis Department, Beijing Chest Hospital, Capital Medical University, Beijing, China. Electronic address: chunaihui1994@sina.com.

PMID: 35405268
DOI: 10.1016/j.ijantimicag.2022.106589

Abstract

Objectives: Linezolid can significantly impact drug-resistant tuberculosis (DR-TB) patient outcomes. However, the long-term use of this drug for TB treatment has been limited by adverse reactions and uncertainty regarding optimal dosage regimens for balancing drug efficacy and safety across different populations. This study attempted to find the optimal dosing regimen of linezolid in different populations.

Methods: A total of 355 blood samples were collected from 126 DR-TB patients. Population pharmacokinetic analysis (using a one-compartment model) and dose simulations were conducted using NONMEM and R software. The ratio between the area under the free drug plasma concentration-time curve to the MIC (fAUC/MIC) of > 119 and trough concentration (C_min) ≤ 2 mg/L served as efficacy and safety targets, respectively, toward the formulation of optimal dosage regimens based on a ≥ 90% cumulative fraction of response.

Results: Body weight and blood urea nitrogen levels were the most significant covariates of apparent volume, while creatinine clearance and haemoglobin level significantly influenced apparent clearance. The probability of target attainment for different dosage regimens was evaluated via Monte Carlo simulation. For subjects with MICs of 0.125, 0.25 and 0.5 mg/L, specific total daily doses of ≥ 300 mg, ≥ 450 mg and ≥ 900 mg were required to reach the target, respectively. Subjects with body weight ≤ 70 kg and MIC ≥ 1 mg/L received a total 1200 mg daily dose to reach the probability of target attainment target. Notably, single dosing was safer than multiple dosing at the same daily dose. The optimal dosage regimens for subjects with body weight < 50 kg and ≥ 50 kg were 450 mg/d and 600 mg/d (once daily), respectively.

Conclusion: Optimal dosage regimens for patients weighing < 50 kg and ≥ 50 kg were 450 mg/d and 600 mg/d, respectively. A single dose was safer than multiple doses.

Keywords: Dosage optimisation; Drug-resistant tuberculosis; Linezolid; Pharmacodynamics; Population pharmacokinetics.

MeSH terms

Anti-Bacterial Agents / therapeutic use
Body Weight
Humans
Linezolid
Microbial Sensitivity Tests
Monte Carlo Method
Tuberculosis, Multidrug-Resistant* / drug therapy

Substances

Anti-Bacterial Agents
Linezolid