title: Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults.
abstract: 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.).
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland fiona.vanobberghen@unibas.ch.
authors.forename: Fiona
authors.initials: F
authors.lastname: Vanobberghen
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Penny
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Duthaler
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Odermatt
authors.affiliation: National Institute of Public Health, Vientiane, Lao People's Democratic Republic.
authors.forename: Somphou
authors.initials: S
authors.lastname: Sayasone
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joel
authors.identifier: 0000-0003-4566-4030
authors.initials: J
authors.lastname: Tarning
mesh_terms: D000328:Adult; D000818:Animals; D000871:Anthelmintics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009889:Opisthorchiasis / Q000188:drug therapy*; D009891:Opisthorchis / Q000472:pathogenicity*; D010655:Phenylenediamines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000871:Anthelmintics; D010655:Phenylenediamines; C056017:tribendimidine