In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine

Abstract

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 in vitro and in vivo 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 (Tmax) 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 (Cmax) 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.

Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review

“…The inhibition of cytochrome (CYP) enzymes by oxantel pamoate has been investigated in two published in vitro studies [ 14 , 16 ]. Oxantel pamoate did not inhibit CYP1A2, CYP2C19 and CYP3A4 (IC 50 > 100 µM) [ 14 ].…”

“…CYP2C9 and CYP2D6 were moderately inhibited by oxantel pamoate (IC 50 = 7.8 µM and CYP2D6) [ 14 ]. In the second study, oxantel pamoate showed an inhibitory activity against CYP2C9 and CYP2D6 [ 16 ]. The inhibition of CYP1A2, CYP2C19, and CYP3A4 by oxantel pamoate was more pronounced than in a previous study by Cowan et al [ 14 ], which reported no interaction of oxantel pamoate with these enzymes.…”

Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects

“…As blood plasma concentrations of IVM in humans were reported to be rarely higher than 100 ng/ml (about 0.1 μM) at a standard oral dose, it might be concluded that IVM, when applied under clinically recommended dose, does not have the potential to cause drug–drug interaction potential on the level of inhibition of P450 enzymes. In addition, it was reported that co-administration of IVM and tribendimidine in rats did not significantly alter the pharmacokinetic behavior of each other and no clinically relevant drug–drug interactions between tribendimidine and Ivermectin on the level of P450 metabolism were observed (Neodo et al 2018 ) .…”

“…In addition, it was reported that co-administration of IVM and tribendimidine in rats did not significantly alter the pharmacokinetic behavior of each other and no clinically relevant drug–drug interactions between tribendimidine and Ivermectin on the level of P450 metabolism were observed (Neodo et al 2018 ) .…”

Current therapeutic applications and pharmacokinetic modulations of ivermectin

“…Ivermectin is combined with different therapeutic agents for improving the spectrum of activity against such parasitic diseases. Tribendimidine-ivermectin has been found to be a promising drug combination for the treatment of soil-transmitted helminthic infections [74].…”