Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Antimicrob Agents Chemother. 2018 Dec 21;63(1). doi: 10.1128/AAC.00762-18. Print 2019 Jan.
Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful and characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STHs and thus represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effects of combinations of ivermectin, oxantel pamoate, and tribendimidine's active metabolite deacylated amidantel (dADT) on cytochrome P450 (CYP450) metabolism were evaluated, followed by a pharmacokinetic analysis of tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for tribendimidine-oxantel pamoate at the CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to moderately increased CYP2D6 inhibition compared to ivermectin or tribendimidine alone. Coadministration of tribendimidine with ivermectin altered neither the time to maximum concentration of drug in plasma () nor the elimination half-lives of dADT, the acetylated derivative of amidantel (adADT), and ivermectin. While the area under the concentration-versus-time curve (AUC) and maximum concentration of drug in plasma () values of dADT, adADT, and ivermectin are reduced by coadministration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in humans.
土壤传播性蠕虫（STH）感染仍然是贫困农村地区的一个主要健康问题。缺乏针对所有 STH 物种的有效药物，引起了对药物组合的兴趣。然而，药物-药物相互作用（DDI）是一个主要关注点，因此需要仔细和特征描述。联合使用三苯双脒加伊维菌素或奥苯达唑可以靶向广泛的 STH，因此代表了一种有前途的治疗选择。然而，尚未研究药物-药物相互作用。因此，评估了伊维菌素、奥苯达唑和三苯双脒的活性代谢物去酰化 amidantel（dADT）的组合对细胞色素 P450（CYP450）代谢的影响，然后对单独使用三苯双脒和伊维菌素以及联合使用时在健康大鼠中的药代动力学进行了分析。奥苯达唑吸收不良，因此不包括在药代动力学分析中。三苯双脒-奥苯达唑组合在 CYP450 代谢水平上没有明显的影响，而三苯双脒和伊维菌素的组合与单独使用伊维菌素或三苯双脒相比，导致 CYP2D6 抑制适度增加。三苯双脒与伊维菌素联合使用既不改变药物在血浆中的达峰时间（），也不改变 dADT、amidantel 的乙酰化衍生物（adADT）和伊维菌素的消除半衰期。虽然 dADT、adADT 和伊维菌素的药时曲线下面积（AUC）和血浆中药物的最大浓度（）值因联合用药而降低，但变化不足以表明已检测到 DDI。需要进一步研究以了解观察到的三苯双脒和伊维菌素之间的相互作用，这种相互作用与 P450 代谢无关，以及其对人类情况的意义。
