Brussee Janneke M, Hiroshige Noemi, Neodo Anna, Coulibaly Jean T, Pfister Marc, Keiser Jennifer
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Antimicrob Agents Chemother. 2021 Jan 20;65(2). doi: 10.1128/AAC.01778-20.
Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine's primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected from 155 school-aged children and adolescents with hookworm infections, following tribendimidine doses ranging from 100 to 400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets than with 50-mg tablets, while the extent of absorption remained unaffected. The identified models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure led to marginal efficacy increase. Combination therapy should be considered, as a 12-fold-higher dose would be needed to achieve 95% ERRs and CRs >90% with tribendimidine alone. Further studies are warranted to evaluate safety of higher tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.
三苯双脒已成功用于治疗钩虫感染，若出现耐药情况，它可作为阿苯达唑的替代药物。我们的目标是：（i）描述三苯双脒的主要代谢产物脱乙酰氨苯达唑（dADT）和次要代谢产物氨苯达唑的乙酰化衍生物（adADT）在学龄儿童和青少年中的药代动力学（PK）特征；（ii）将暴露量与抗钩虫疗效联系起来；（iii）评估儿童三苯双脒药物治疗是否可以进一步改进。首先，基于从155名感染钩虫的学龄儿童和青少年中采集的干血斑样本，建立了群体PK模型，这些儿童和青少年服用的三苯双脒剂量范围为100至400毫克。其次，进行了暴露-反应分析，以将活性代谢产物dADT与治愈率（CRs）和虫卵减少率（ERRs）联系起来。第三，进行模拟以确定与治愈率>90%相关的治疗策略。一个带有转运室的二室模型描述了观察到的吸收延迟，该模型充分描述了dADT和adADT的PK数据。纳入了异速生长标度以考虑生长发育情况。200毫克片剂的吸收率比50毫克片剂低56%，而吸收程度不受影响。所确定的将dADT暴露量与ERRs和CRs联系起来的模型显示曲线较平缓，因为暴露量增加导致疗效仅略有增加。应考虑联合治疗，因为仅使用三苯双脒要达到95%的ERRs和治愈率>90%，所需剂量要高出12倍。有必要进一步研究以评估更高剂量三苯双脒以及与其他驱虫剂联合治疗的安全性，以改进钩虫感染儿童的治疗策略。
