Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, the Netherlands.
Drugs for Neglected Diseases initiative, Geneva, Switzerland.
PLoS Negl Trop Dis. 2024 Apr 19;18(4):e0012078. doi: 10.1371/journal.pntd.0012078. eCollection 2024 Apr.
With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease.
Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling.
Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease.
This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.
目前针对内脏利什曼病（VL）的治疗方法，一部分患者会出现寄生虫复发的情况。了解寄生虫动力学对于提高治疗效果和预测 VL 患者的疾病复发至关重要。本研究旨在描述不同抗利什曼病治疗期间和治疗后血液中循环利什曼寄生虫的动力学特征，并寻找疾病临床复发的预测因子。
本研究结合了三项临床试验的数据，这些试验中，东非 VL 患者接受了各种抗利什曼病的治疗方案。使用实时定量 PCR（qPCR）在治疗前、治疗期间和治疗后长达六个月内对全血中的利什曼原虫动基体 DNA 进行定量。使用非线性混合效应建模开发了一个综合的群体药代动力学-药效动力学模型。
寄生虫增殖最好用指数增长模型来描述，体内寄生虫倍增时间为 7.8 天（RSE 为 12%）。芬西诺唑、脂质体两性霉素 B、葡萄糖酸锑钠和米替福新对寄生虫的杀伤作用最好用线性模型来描述，这些模型直接将药物浓度与寄生虫消除率相关联。治疗后，假设寄生虫的生长受到宿主免疫系统的抑制，由治疗后时间驱动的 Emax 模型来描述。无法确定免疫反应的起始和幅度的高变异性的预测因子。基于模型的个体预测在治疗开始后第 28 天和第 56 天的血液寄生虫负荷可以预测疾病的临床复发。
该半机械动力学药代动力学-药效动力学模型充分描述了治疗期间和治疗后的血液寄生虫动力学，并揭示了治疗开始后第 28 天和第 56 天的高血液寄生虫负荷是 VL 复发的早期迹象，这可能是评估临床试验中治疗方案治疗效果的有用生物标志物。
