苯并硝唑在慢性恰加斯病小鼠模型中的药动学-药效学建模及其抗锥虫体活性。

IF 3.4 2区 医学 Q1 PARASITOLOGY
PLoS Neglected Tropical Diseases Pub Date : 2025-05-13 eCollection Date: 2025-05-01 DOI:10.1371/journal.pntd.0012968
Frauke Assmus, Ayorinde Adehin, Richard M Hoglund, Amanda Fortes Francisco, Michael D Lewis, John M Kelly, Susan A Charman, Karen L White, David M Shackleford, Fanny Escudié, Eric Chatelain, Ivan Scandale, Joel Tarning
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引用次数: 0

摘要

背景:恰加斯病是由克氏锥虫引起的一种被忽视的热带感染,迫切需要改进治疗方法。作为一线治疗手段,苯并硝唑在慢性感染中存在耐受性差、疗效不一等严重局限性。为了优化给药方案,更好地了解苯并硝唑的药代动力学/药效学(PK/PD)关系至关重要。本研究旨在研究苯并硝唑在小鼠体内的群体药动学特性,并探讨其与克氏锥虫感染小鼠抗锥虫体活性的关系。方法/主要发现:利用高灵敏度的体内生物发光成像(BLI)技术,对118只患有慢性克氏t细胞感染的BALB/c小鼠进行了抗锥虫体活性评估。苯并硝唑以10 - 100mg /kg的剂量给药5-20天。采用非线性混合效应模型评价了苯并硝唑在52只未感染BALB/c小鼠体内的药动学特性。采用logistic回归和偏最小二乘判别分析方法,对模拟苯并硝唑暴露与无菌寄生虫治愈之间的关系进行了评价。苯并硝唑在小鼠体内的药代动力学由一阶吸收的单室配置模型很好地描述,较高的剂量与较慢的吸收相关。单变量逻辑回归显示药物暴露与寄生虫治愈概率之间存在显著相关性。如果给予苯并硝唑至少5天,总血浆暴露、IC90以上时间和血药浓度峰值均与疗效密切相关。结论/意义:这是第一个利用临床前BLI数据成功量化苯并硝唑在克氏锥虫感染小鼠体内的剂量-反应关系的研究。我们的研究结果强调,由于PK/PD指标参数之间的高度共线性,区分药效的PK/PD驱动因素的复杂性,我们建议在未来的研究中进行剂量分离研究。使用BLI模型研究PK/PD关系提供了有价值的见解,有助于通过寄生虫感染的终点评估生成假设。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease.

Background: There is an urgent need for improved treatments for Chagas disease, a neglected tropical infection caused by the protozoan parasite Trypanosoma cruzi. Benznidazole, the first line therapy, has severe limitations such as poor tolerability and variable efficacy in the chronic stage of infection. To optimize dosing regimens, a better understanding of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for benznidazole is crucial. This study aimed to characterize the population pharmacokinetic properties of benznidazole in mice and investigate the relationship between exposure and antitrypanosomal activity in T. cruzi infected mice.

Methodology/principal findings: Antitrypanosomal activity was assessed in 118 BALB/c mice with chronic-stage T. cruzi infection, utilizing highly sensitive in vivo bioluminescence imaging (BLI). Benznidazole was administered at doses ranging from 10 to 100 mg/kg for 5-20 days. The pharmacokinetic properties of benznidazole were evaluated in 52 uninfected BALB/c mice using nonlinear mixed-effects modeling. The relationship between simulated benznidazole exposure and sterile parasitological cure in the BLI experiments was evaluated by logistic regression and partial least squares - discriminant analysis. Benznidazole pharmacokinetics in mice were well described by a one-compartment disposition model with first-order absorption, with higher doses associated with slower absorption. Univariate logistic regression revealed a significant correlation between drug exposure and the probability of parasitological cure. Total plasma exposure, time above IC90 and peak plasma concentration were all strongly associated with efficacy, provided that benznidazole was administered for at least 5 days.

Conclusions/significance: This is the first study to successfully quantify the dose-response relationship for benznidazole in T. cruzi-infected mice using preclinical BLI data. Our results underscore the complexity of distinguishing PK/PD drivers of efficacy due to high collinearity between PK/PD index parameters, and we propose dose-fractionation studies for future research. Studying the PK/PD relationship using the BLI model provides valuable insights, aiding hypothesis generation through endpoint assessment of parasite infection.

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来源期刊
PLoS Neglected Tropical Diseases
PLoS Neglected Tropical Diseases PARASITOLOGY-TROPICAL MEDICINE
自引率
10.50%
发文量
723
期刊介绍: PLOS Neglected Tropical Diseases publishes research devoted to the pathology, epidemiology, prevention, treatment and control of the neglected tropical diseases (NTDs), as well as relevant public policy. The NTDs are defined as a group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of low-income and middle-income countries. Their impact on child health and development, pregnancy, and worker productivity, as well as their stigmatizing features limit economic stability. All aspects of these diseases are considered, including: Pathogenesis Clinical features Pharmacology and treatment Diagnosis Epidemiology Vector biology Vaccinology and prevention Demographic, ecological and social determinants Public health and policy aspects (including cost-effectiveness analyses).
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