The Journal of antimicrobial chemotherapy · 2025
Population pharmacokinetic model of linezolid and its metabolite PNU-142300 in elderly patients.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Chen Xianglong, Yang LiJuan, Zhang Qian, Zhuang Zhiwei, Li TongTong, Yuan Yunlong, Duan Lufen, Shi Lu, Huang Shenjia, Zhao Hanzhen, Lu Jian, Li Jingjing, Fan Jinwei, Yu Yanxia, Tang Lian, Xu Jinhui
Аннотация
BACKGROUND AND OBJECTIVES: Elderly patients are at an increased risk of supratherapeutic linezolid exposure, and elevated trough concentrations of linezolid and its metabolite (PNU-142300) are associated with the development of linezolid-induced thrombocytopenia. Clarifying the population pharmacokinetic (PPK) characteristics of linezolid and PNU-142300 in this population is critical for optimizing therapeutic strategies. This study aimed to develop a PPK model for linezolid and PNU-142300 in elderly patients to guide dose adjustments and mitigate thrombocytopenia risk.
METHODS: Patients aged ≥65 years receiving linezolid therapy were enrolled. Concentrations of linezolid and PNU-142300 were quantified using LC-MS/MS. Covariate analysis was conducted via stepwise forward inclusion and backward elimination. Model evaluation included goodness-of-fit plots, prediction-corrected visual predictive checks, and nonparametric bootstrap validation. Monte Carlo simulations were performed to identify optimal dosing regimens.
RESULTS: A total of 149 concentrations from 114 patients were analysed. Creatinine clearance (CLCr) significantly influenced the clearance of both linezolid and PNU-142300. Population mean estimates for clearance were 2.02 L/h (linezolid) and 1.57 L/h (PNU-142300), with an equal volume of distribution of 31.17 L. The model demonstrated robust stability and predictive performance. For patients with CLCr of 15-29 mL/min, 200 mg q12h achieved optimal linezolid exposure, with a 78.6% probability of maintaining PNU-142300 below the toxicity threshold. For patients with CLCr of 30-89 mL/min, 200 mg q8h provided therapeutic exposure with >80% probability of avoiding metabolite toxicity.
CONCLUSIONS: This first PPK model of linezolid and PNU-142300 in elderly patients supports individualized dosing to reduce thrombocytopenia risk. Linezolid dose reduction may be necessary in elderly patients.
METHODS: Patients aged ≥65 years receiving linezolid therapy were enrolled. Concentrations of linezolid and PNU-142300 were quantified using LC-MS/MS. Covariate analysis was conducted via stepwise forward inclusion and backward elimination. Model evaluation included goodness-of-fit plots, prediction-corrected visual predictive checks, and nonparametric bootstrap validation. Monte Carlo simulations were performed to identify optimal dosing regimens.
RESULTS: A total of 149 concentrations from 114 patients were analysed. Creatinine clearance (CLCr) significantly influenced the clearance of both linezolid and PNU-142300. Population mean estimates for clearance were 2.02 L/h (linezolid) and 1.57 L/h (PNU-142300), with an equal volume of distribution of 31.17 L. The model demonstrated robust stability and predictive performance. For patients with CLCr of 15-29 mL/min, 200 mg q12h achieved optimal linezolid exposure, with a 78.6% probability of maintaining PNU-142300 below the toxicity threshold. For patients with CLCr of 30-89 mL/min, 200 mg q8h provided therapeutic exposure with >80% probability of avoiding metabolite toxicity.
CONCLUSIONS: This first PPK model of linezolid and PNU-142300 in elderly patients supports individualized dosing to reduce thrombocytopenia risk. Linezolid dose reduction may be necessary in elderly patients.