Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00959-18. Print 2018 Sep.
Tribendimidine is a broad-spectrum anthelminthic available in China, which is currently being pursued for U.S. Food and Drug Administration approval for soil-transmitted helminth infections. Pharmacokinetic (PK) studies with tribendimidine in children, the main target group for treatment programs, have not been conducted to date. In the framework of a dose-ranging study in hookworm-infected school-aged children in Côte d'Ivoire, children were treated with either 100, 200, or 400 mg tribendimidine. Dried blood spot samples were collected up to 22 h after treatment. The active metabolite, deacetylated amidantel (dADT) and its metabolite acylated dADT (adADT) were quantified using liquid chromatography tandem mass spectrometry. PK parameters were calculated using a noncompartmental model, and univariate logistic regression was applied using maximal blood concentrations () and area under the blood concentration-time curve for 0 to 22 h (AUC) as predictors of drug efficacy. Dried blood spot samples of 101 children were analyzed. We observed a less than proportional and proportional exposure in dADT's median and AUC, respectively, following administration of 100 mg ( = 853 ng/ml; AUC = 3,019 h · ng/ml) and 400 mg ( = 2,275 ng/ml; AUC = 12,530 h · ng/ml) tribendimidine. There were large, dose-independent variations in the time to () and ratios of dADT to adADT. We did not detect an influence of or AUC of dADT or adADT on drug efficacy or adverse events. Since our study population was bearing hookworm infection of mainly low intensity, additional studies with heavy intensity infections might be required to confirm this observation.
三苯双脒是一种广谱驱虫药，已在中国上市，目前正寻求获得美国食品和药物管理局批准，用于治疗土壤传播性蠕虫感染。迄今为止，尚未在儿童（治疗方案的主要目标人群）中开展三苯双脒的药代动力学（PK）研究。在科特迪瓦钩虫感染学龄儿童的剂量范围研究中，儿童分别接受 100、200 或 400 mg 三苯双脒治疗。治疗后至 22 小时采集干血斑样本。使用液相色谱串联质谱法定量分析活性代谢物去乙酰化 amidantel（dADT）及其代谢物酰化 dADT（adADT）。使用非房室模型计算 PK 参数，并应用单变量逻辑回归，将最大血药浓度（）和 0 至 22 小时血药浓度-时间曲线下面积（AUC）作为药物疗效的预测因子。分析了 101 名儿童的干血斑样本。我们观察到，100 mg （=853 ng/ml；AUC=3019 h·ng/ml）和 400 mg （=2275 ng/ml；AUC=12530 h·ng/ml）三苯双脒给药后，dADT 的中位数和 AUC 呈不成比例和比例暴露。和 adADT 的比例。和 dADT 至 adADT 的比值存在较大的、剂量独立的变化。我们未发现 dADT 或 adADT 的或 AUC 对药物疗效或不良事件有影响。由于我们的研究人群主要感染低强度的钩虫，可能需要进行更多高强度感染的研究来证实这一观察结果。
