Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections
| Autor: | Jean T. Coulibaly, Marc Pfister, Janneke M. Brussee, Jessica D. Schulz, Anna Neodo, Jennifer Keiser |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Ancylostomatoidea medicine.medical_specialty Combination therapy Adolescent 030231 tropical medicine Population Clinical Therapeutics Phenylenediamines Tribendimidine 03 medical and health sciences Hookworm Infections 0302 clinical medicine Pharmacotherapy Ivermectin Pharmacokinetics Internal medicine parasitic diseases medicine Animals Humans Pharmacology (medical) education Pharmacology Anthelmintics 0303 health sciences education.field_of_study 030306 microbiology business.industry Combination chemotherapy Infectious Diseases business medicine.drug |
| Zdroj: | Antimicrob Agents Chemother |
| Popis: | In the treatment of 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 in combination with ivermectin or oxantel pamoate, (ii) evaluate possible drug-drug interactions (DDI), (iii) link exposure to response, and (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 a 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 arm and the arm including the combination with oxantel pamoate, E(max) models adequately described the correlation between dADT exposure and probability of being cured, with required exposures 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 of >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. |
| Databáze: | OpenAIRE |
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