治疗耐药非结核分枝杆菌肺病患者中硫酸卷曲霉素脂质体吸入混悬液的群体药代动力学评价。
Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease.
机构信息
Institute for Clinical Pharmacodynamics, Inc, 242 Broadway, Schenectady, NY, USA.
Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
出版信息
Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):277-287. doi: 10.1007/s13318-020-00669-7. Epub 2021 Feb 17.
BACKGROUND AND OBJECTIVES
Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease.
METHODS
In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg.
RESULTS
Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (C) was < 2 mg/L and median area under the concentration-time curve (AUC) was < 20 mg·h/L, suggesting low systemic exposure at both time points. Exposure estimates were similar between Japanese and White patients. The median unchanged amikacin fraction excreted in urine was < 10% of inhaled dose throughout the TR02-112 study, indicating that relatively small amounts reached systemic circulation. Median t was 5.5 h. Amikacin concentrations were much higher in sputum than in serum, demonstrating the ability to achieve higher drug concentration at the site of infection. Median sputum amikacin concentrations in the CONVERT study were high at 1-4 h postdose (range 242-426 μg/g) and decreased by 8 h (median 7 μg/g).
CONCLUSIONS
Systemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).
背景和目的
使用氨基糖苷类抗生素阿米卡星治疗难治性非结核分枝杆菌（NTM）肺病，由于其全身毒性限制了其应用。本研究采用来自两项随机试验的数据建立群体药代动力学模型，以评估治疗难治性 NTM 肺病患者每日一次应用阿米卡星脂质体吸入混悬液（ALIS）的药代动力学特征。
方法
在两项研究（TR02-112 期和 CONVERT 期）中，痰培养阳性的 M. avium complex 患者（两项研究）或 M. abscessus 患者（TR02-112 期），尽管接受了至少 6 个月的基于指南的治疗，但治疗仍未缓解，给予每日一次 ALIS 590 mg 治疗。
结果
53 例患者（28 例日本患者；25 例白种人患者）接受了评估。在每日治疗开始时和治疗 6 个月后，中位最大浓度（C）<2 mg/L，中位浓度-时间曲线下面积（AUC）<20 mg·h/L，提示在两个时间点的全身暴露均较低。日本患者和白种人患者的暴露估计值相似。在整个 TR02-112 研究中，尿中未改变的阿米卡星排泄分数中位数<吸入剂量的 10%，表明进入全身循环的量相对较小。中位 t 为 5.5 h。阿米卡星在痰液中的浓度远高于血清中的浓度，表明能够在感染部位达到更高的药物浓度。在 CONVERT 研究中，中位痰液阿米卡星浓度在给药后 1-4 h 较高（范围 242-426 μg/g），8 h 后下降（中位数 7 μg/g）。
结论
在治疗难治性 NTM 肺病患者中，每日一次应用 ALIS 后，血清和尿液中的阿米卡星全身暴露明显低于先前报道的阿米卡星的全身暴露。
试验注册
ClinicalTrials.gov NCT01315236（2011 年 3 月 15 日注册）和 NCT02344004（2015 年 1 月 22 日注册）。
Zotero 插件