Effects of ivermectin and oxantel pamoate on tribendimidine: in vitro and in vivo drug-drug interaction study [Experimental Therapeutics]

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 the interest in drug combinations. Drug-drug interactions are, however, of major concern so that careful in vitro and in vivo characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STH and thus, represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effect of combinations of ivermectin, oxantel pamoate and tribendimidine's active metabolite deacylated amidantel (dADT) on the CYP450 metabolism was 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 CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to a moderately increased CYP2D6 inhibition as compared to ivermectin or tribendimidine alone. Co-administration of tribendimidine with ivermectin altered neither the T_max nor elimination half-lives of dADT, adADT and ivermectin. While the AUCs and C_max of dADT, adADT and ivermectin are reduced by co-administration, 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 human.

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