Cargando…

Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults

There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini. Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single or...

Descripción completa

Detalles Bibliográficos
Autores principales: Vanobberghen, Fiona, Penny, Melissa A., Duthaler, Urs, Odermatt, Peter, Sayasone, Somphou, Keiser, Jennifer, Tarning, Joel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038332/
https://www.ncbi.nlm.nih.gov/pubmed/27431233
http://dx.doi.org/10.1128/AAC.00655-16
_version_ 1782455880081473536
author Vanobberghen, Fiona
Penny, Melissa A.
Duthaler, Urs
Odermatt, Peter
Sayasone, Somphou
Keiser, Jennifer
Tarning, Joel
author_facet Vanobberghen, Fiona
Penny, Melissa A.
Duthaler, Urs
Odermatt, Peter
Sayasone, Somphou
Keiser, Jennifer
Tarning, Joel
author_sort Vanobberghen, Fiona
collection PubMed
description There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini. Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.)
format Online
Article
Text
id pubmed-5038332
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher American Society for Microbiology
record_format MEDLINE/PubMed
spelling pubmed-50383322016-10-13 Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults Vanobberghen, Fiona Penny, Melissa A. Duthaler, Urs Odermatt, Peter Sayasone, Somphou Keiser, Jennifer Tarning, Joel Antimicrob Agents Chemother Pharmacology There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini. Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.) American Society for Microbiology 2016-09-23 /pmc/articles/PMC5038332/ /pubmed/27431233 http://dx.doi.org/10.1128/AAC.00655-16 Text en Copyright © 2016 Vanobberghen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacology
Vanobberghen, Fiona
Penny, Melissa A.
Duthaler, Urs
Odermatt, Peter
Sayasone, Somphou
Keiser, Jennifer
Tarning, Joel
Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults
title Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults
title_full Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults
title_fullStr Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults
title_full_unstemmed Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults
title_short Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults
title_sort population pharmacokinetic modeling of tribendimidine metabolites in opisthorchis viverrini-infected adults
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038332/
https://www.ncbi.nlm.nih.gov/pubmed/27431233
http://dx.doi.org/10.1128/AAC.00655-16
work_keys_str_mv AT vanobberghenfiona populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults
AT pennymelissaa populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults
AT duthalerurs populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults
AT odermattpeter populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults
AT sayasonesomphou populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults
AT keiserjennifer populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults
AT tarningjoel populationpharmacokineticmodelingoftribendimidinemetabolitesinopisthorchisviverriniinfectedadults