To treat hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine's metabolites in adolescents receiving tribendimidine monotherapy, or a combination with ivermectin or oxantel pamoate, (ii) evaluate possible drug-drug interactions (DDI), (iii) link exposure to response, aiming to (iv) identify a treatment strategy associated with high efficacy, i.e. >90% cure rates (CRs), utilizing model-based simulations.
A population pharmacokinetic model was developed for tribendimidine's primary and secondary metabolites dADT and adADT in 54 hookworm-positive adolescents, with combination therapy evaluated as possible covariate. Subsequently, an exposure-response analysis was performed utilizing CRs as response markers. Simulations were performed to identify a treatment strategy to achieve >90% CRs.
A two-compartmental model best described metabolite disposition. No pharmacokinetic DDI was identified with ivermectin or oxantel pamoate. All participants receiving tribendimidine plus ivermectin were cured. For the monotherapy and combination with oxantel pamoate arm, Emax models adequately described the correlation between dADT exposure and probability to be cured, with a required exposure to achieve 50% of maximum effect of 39.6 and 15.6 nmol/mL*h, respectively.
Based on our simulations an unrealistically high monotherapy tribendimidine dose would be necessary to achieve CRs >90%, while combination therapy with ivermectin would meet this desired target product profile. Further clinical studies should be launched to develop this combination for the treatment of hookworm and other helminth infections.
Combination Therapy of Bortezomib with Novel Targeted Agents: An Emerging Treatment Strategy
