Pharmacokinetics of a pediatric tribendimidine dose-finding study to treat hookworm infection in African children [PublishAheadOfPrint]

Tribendimidine is a broad-spectrum anthelmintic available in China, which is currently being pursued for US 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 either treated with 100 mg, 200 mg, or 400 mg tribendimidine. Dried blood spot samples were collected up to 22 hours 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 (C_max) and area under the blood concentration-time curve (AUC_0-22h) 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 C_max and AUC_0-22h, respectively, following administration of 100 mg (C_max=853 ng/ml; AUC_0-22h =3,019 h*ng/ml) and 400 mg (C_max=2,275ng/ml; AUC_0-22h =12,530 h*ng/ml) tribendimidine. There were large, dose-independent variations in the time to C_max (T_max) and ratios of dADT to adADT. We did not detect an influence of C_max or AUC_0-22h of dADT or adADT on drug efficacy or adverse events. Since our study population was bearing hookworm infection of mainly low intensity, additional studies in heavy intensity infections might be required to confirm this observation.

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