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Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections.

ABSTRACT: Opisthorchiasis, caused by the foodborne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao People's Democratic Republic, pharmacokinetic samples were obtained from 125 adult and adolescent O. viverrini-infected patients treated with 400 mg tribendimidine following the design of a sparse sampling scheme at 20 min and 2, 7.75, 8, and 30 h after treatment using dried blood spot sampling. Pharmacokinetic data for the metabolites deacetylated amidantel (dADT) and acetylated dADT (adADT) were pooled with data from two previous ascending-dose trials and evaluated using nonlinear mixed-effects modeling. The observed pharmacokinetic data were described using a flexible transit absorption model for the active metabolite dADT, followed by one-compartment disposition models for both metabolites. Significant covariates were age, body weight, formulation, and breaking of the enteric coating on the tablets. There were significant associations between O. viverrini cure and both the dADT maximum concentration and the area under the concentration-time curve (P < 0.001), with younger age being associated with a higher probability of cure. Modeling and simulation of exposures in patients with different weight and age combinations showed that an oral single dose of 400 mg tribendimidine attained therapeutic success in over 90% of adult patients. Our data confirmed that tribendimidine could be a valuable novel alternative to the standard treatment, praziquantel, for the treatment of O. viverrini infections.

SUBMITTER: Meister I

PROVIDER: S-EPMC6437521 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections.

Meister Isabel I Assawasuwannakit Piyanan P Vanobberghen Fiona F Penny Melissa A MA Odermatt Peter P Sayasone Somphou S Huwyler Jörg J Tarning Joel J Keiser Jennifer J

Antimicrobial agents and chemotherapy 20190327 4

Opisthorchiasis, caused by the foodborne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao People's Democratic Republic, pharmacokinetic samples were obtained from 125 adult and adolescent O. viverrini-infected patients treated with 400 mg tribendimidine following the design of a sparse sampling scheme at 20 min and 2, 7.75, 8, and 30 h after treatment using dried blood spot samplin ...[more]

PMID: 30718244

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Project description:Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (Tmax) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) of dADT to the AUC0- 24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (Cmax) and AUC0-24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.).

Project description:BackgroundOpisthorchis viverrini infection is highly prevalent in northeast Thailand. This liver fluke is classified as a carcinogen due to its causal links with cholangiocarcinoma (CCA) development. Although treatment with praziquantel (PZQ) effectively cures O. viverrini infection, the prevalence remains high due to the traditional consumption of raw fish. Therefore, re-infection is common in the endemic community, leading to severe hepato-biliary morbidities including the fatal CCA. In this study, we evaluate the association between the frequency of previous PZQ treatment and current O. viverrini infections among Thai adults living in the endemic area of northeast Thailand.MethodsThis study includes all participants who were screened for O. viverrini infection in the Cholangiocarcinoma Screening and Care Program (CASCAP), northeast Thailand. History of PZQ treatment was recorded using a health questionnaire. O. viverrini infections were diagnosed using urine antigen detection. Associations between PZQ and O. viverrini were determined by adjusted odds ratio (aOR) and 95% confidence interval (CI) using multiple logistic regression.ResultsAmong participants, 27.7% had previously been treated once with PZQ, 8.2% twice, 2.8% three times, and 3.5% more than three times. Current O. viverrini prevalence was 17% (n = 524). Compared with participants who never used PZQ, the aOR for infection among those who used the drug once was 1.09 (95% CI: 0.88-1.37), twice was 1.19 (95% CI: 0.85-1.68), three times was 1.28 (95% CI: 0.74-2.21), and more than three times was 1.86 (95% CI: 1.18-2.93; P = 0.007).ConclusionsThe population with a frequent history of PZQ use and still continued raw fish consumption showed high levels of repeated reinfection with O. viverrini. They were infected, treated and re-infected repeatedly. These findings suggest that certain participants continue raw fish consumption even after previous infection. This is a particular problem in highly endemic areas for O. viverrini and increases the risk of CCA.

Dataset Information

Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections.

Publications

Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of <i>Opisthorchis viverrini</i> Infections.

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