tribendimidine and Opisthorchiasis

Opisthorchiasis, caused by the foodborne trematode

Topics: Adolescent; Adult; Aged; Animals; Antiplatyhelmintic Agents; Female; Humans; Male; Middle Aged; Models, Biological; Opisthorchiasis; Opisthorchis; Phenylenediamines; Young Adult

Praziquantel is the only option for treatment of the liver fluke infection Opisthorchis viverrini. Tribendimidine could be an alternative drug. We aimed to assess the efficacy and safety of a single, oral dose of tribendimidine, compared with praziquantel administered in two doses, in participants with O viverrini infection.. We did an open-label, randomised, non-inferiority, phase 2 trial in children (8-14 years) and adolescents and adults (≥15 years) in Champasack province, southern Laos. Participants infected with O viverrini were randomly assigned (1:1), via a computer-generated block-randomisation procedure (block sizes of two, four, and six), to receive a single, oral dose of tribendimidine (200 mg for children, 400 mg for adolescents and adults) or two oral doses of praziquantel (50 mg/kg bodyweight and 25 mg/kg bodyweight, 6 h apart). Physicians assessing adverse events and laboratory personnel were masked to treatment allocation, but the investigators administering treatment and the participants could have recognised the treatment group based on differences in the number, appearance, and odour of the tablets. The primary outcomes were cure rate, defined as no parasite eggs in stool at 3 weeks' follow-up, and egg reduction rate. We did available-case analysis of all participants with primary endpoint data. The non-inferiority margin for the difference in cure rates between the groups was pre-specified as -3 percentage points. Adverse events were monitored at 3 h and 24 h after treatment. This trial is registered, number ISRCTN96948551.. Between Feb 1, and April 30, 2014, we assigned 607 participants with confirmed O viverrini infection to receive tribendimidine (n=300) or praziquantel (n=307). 11 participants (five in the tribendimidine group and six in the praziquantel group) did not provide stool samples at 3 weeks' follow-up and were excluded from the available-case analysis. 276 (93·6%) of 295 participants in the tribendimidine group were cured compared with 293 (97·3%) of 301 participants in the praziquantel group. The difference in cure rates between the two groups was -3·8 percentage points (95% CI -7·1 to -0·4), thus the lower limit of the confidence interval exceeded the non-inferiority margin. In both treatment groups, egg reduction rates were 99·9%. Adverse events were of mild and moderate intensity and were more frequent in the praziquantel group than in the tribendimidine group (odds ratio 4·5, 95% CI 3·2-6·3; p<0·0001). The most frequent adverse events were headache, vertigo, nausea, and fatigue.. Tribendimidine has a slightly lower cure rate than praziquantel and non-inferiority was not shown. However, tribendimidine has a similar egg reduction rate to praziquantel and leads to fewer adverse events and thus might complement praziquantel in O viverrini control programmes, particularly in settings co-endemic for hookworm.. Joint Global Health Trials scheme from the Wellcome Trust, Department for International Development, and Medical Research Council.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Animals; Anthelmintics; Child; Drug-Related Side Effects and Adverse Reactions; Feces; Female; Humans; Laos; Male; Middle Aged; Opisthorchiasis; Opisthorchis; Parasite Egg Count; Phenylenediamines; Praziquantel; Treatment Outcome; Young Adult

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.).

Topics: Adult; Animals; Anthelmintics; Female; Humans; Male; Middle Aged; Models, Biological; Opisthorchiasis; Opisthorchis; Phenylenediamines; Treatment Outcome

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.).

Topics: Adolescent; Adult; Aged; Animals; Anthelmintics; Dried Blood Spot Testing; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Opisthorchiasis; Opisthorchis; Phenylenediamines; Tandem Mass Spectrometry; Treatment Outcome; Young Adult

Treatment of the liver fluke infection Opisthorchis viverrini relies exclusively on praziquantel. Tribendimidine could be an alternative treatment option. We aimed to assess the efficacy and safety of ascending single, oral doses of tribendimidine in patients with O viverrini infection.. We did two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials in children (aged 8-14 years) and adults and adolescents (≥15 years) in three O viverrini endemic villages in Champasack province, southern Laos. Patients with O viverrini infection were randomly assigned, via a computer-generated central block-randomisation procedure, with block sizes of three (study 1) and four, eight, and 12 (study 2), to receive oral tribendimidine at doses of 200 mg, 400 mg, or 600 mg in a 1:1:1 ratio (adults and adolescents in study 1); 25 mg, 50 mg, 100 mg, or 200 mg (four 50 mg tablets) in a 1:1:1:1 ratio (adults and adolescents in study 2); or 100 mg, 200 mg, or 400 mg in a 1:1:1 ratio (children in study 1). One non-randomised group of children received tribendimidine 50 mg (study 2). Participants, investigators, and laboratory technicians doing the diagnostic assessments were masked to group assignment, but the investigator administering treatment could have recognised the treatment group based on the number of tablets. The primary objective was to estimate the dose-response relation in terms of cure rate and egg reduction rate. We did available-case analysis of all patients with primary endpoint data. We predicted dose-response associations with Emax models. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN96948551.. Between Oct 25, 2012, and Nov 5, 2013, 318 adolescents and adults were randomly assigned to seven tribendimidine dose groups: 200 mg (n=51), 400 mg (n=49), or 600 mg (n=47) in study 1, and 25 mg (n=39), 50 mg (n=47), 100 mg (n=44), or 200 mg (four 50 mg tablets; n=41) in study 2. 128 children were randomly assigned to receive tribendimidine 100 mg (n=44), 200 mg (n=40), or 400 mg (n=44) in study 1; 39 children were enrolled and received tribendimidine 50 mg in study 2. In adolescents and adults, the number of patients cured increased with increasing tribendimidine doses up to 100 mg: ten of 39 patients (25·6%, 95% CI 13·0-42·1) were cured in the 25 mg group, 20 of 47 patients (42·6%, 28·3-57·8) were cured in the 50 mg group, and 34 of 44 patients (77·3%, 62·2-88·5) were cured in the 100 mg group; geometric mean egg reduction rates were 86·9% (95% CI 74·8-93·4), 95·9% (92·7-97·7), and 99·1% (98·2-99·7), respectively. The 200 mg dose resulted in cure in 40 of 47 (83·0%, 69·2-92·5) adolescents and adults given the 200 mg tablet and 25 of 41 (61·0%, 95% CI 44·5-75·8) of those given four 50 mg tablets; the 400 mg dose resulted in cure in 43 of 47 patients (91·5%, 79·6-97·6) and the 600 mg dose resulted in cure in 36 of 45 patients (80·0%, 65·4-90·4). Corresponding egg reduction rates were 99·8% (95% CI 99·7-100·0) with one 200 mg tablet, 97·9% (95·9-99·2) with four 50 mg tablets, 99·9% (99·8-100·0) with 400 mg, and 99·8% (99·6-99·9) with 600 mg. The Emax model predicted an egg reduction rate of 99·0% (95% CI 95·7-99·8) at 111 mg in adolescents and adults. 50 mg tribendimidine had moderate efficacy in children, with cure recorded in 16 of 39 patients (41·0%, 95% CI 25·6-57·9). The 100 mg dose resulted in cure in 40 of 44 children (98·9%, 95% CI 78·3-97·5) and an egg reduction rate of 99·7% (95% CI 99·0-100·0), with no increased efficacy at higher doses. The Emax model predicted an egg reduction rate of 99·0% (95% CI 92·2-99·9) at 215 mg. Few adverse events were reported and were mostly mild, with few moderate and no serious events. The most common adverse events 3 h after treatment in adolescents and adults were vertigo (n=35 [11%]), headache (n=9 [3%]), nausea (n=6 [2%]), and fatigue (n=4 [1%]), and in children were headache (n=3 [2%]), vertigo (n=2 [1%]), and fatigue (n=2 [1%]).. Tribendimidine has excellent efficacy and tolerability at doses of 100 mg and above. Our study included mainly adults and children with low-intensity O viverrini infection; future studies should assess the efficacy of tribendimidine in patients with infections of moderate and high intensity.. Department for International Development, Medical Research Council, Wellcome Trust Joint Global Health Trials Scheme.

Topics: Adolescent; Adult; Animals; Child; Dose-Response Relationship, Drug; Female; Humans; Loa; Male; Middle Aged; Opisthorchiasis; Opisthorchis; Parasite Egg Count; Phenylenediamines; Single-Blind Method; Treatment Outcome

Praziquantel is the only drug available for treatment of Opisthorchis viverrini, although in-vivo studies point to activity of mefloquine, artesunate, and tribendimidine against this liver fluke. We aimed to assess the efficacy and safety of these drugs compared with that of praziquantel in patients with O viverrini infection.. We did a randomised open-label trial between February and April, 2010, in the Saysetha district, Attapeu Province, Laos. Eligible patients were school children aged 10-15 years who had O viverrini infections. Patients were randomly assigned to one of five different treatment groups by use of a computer-generated randomisation code. We assessed efficacy as cure rate and egg reduction rate in intention-to-treat and per-protocol analyses. The trial was registered with Current Controlled Trials, ISRCTN23425032.. 125 children were randomly assigned: 25 received mefloquine, 24 artesunate, 24 mefloquine-artesunate, 27 tribendimidine, and 25 praziquantel. 19 patients were lost to follow-up. In the intention to treat analysis, 14 patients receiving praziquantel were cured compared with none with mefloquine, one with artesunate (odds ratio 0·03, 95% CI 0·004-0·29), one with mefloquine-artesunate (0·03, 0·004-0·29), and 19 with tribendimidine (1·87, 0·60-5·85). Egg reduction rate was 98·4% for praziquantel, 30·2% for mefloquine (egg reduction-rate ratio 1·61, 95% CI 0·21-0·72), 31·5% for artesunate (0·43, 0·23-0·80), 41·3% for mefloquine-artesunate (0·60, 0·31-1·10), and 99·3% for tribendimidine (1·00, 0·44-2·30). Most adverse events were mild or moderate and affected all treatment groups; serious adverse events--vertigo, nausea, vomiting, and anxiety--were reported only by patients taking mefloquine or mefloquine-artesunate.. Tribendimidine seems to be at least as efficacious as the drug of choice, praziquantel, for the treatment of O viverrini infections; both drugs were well tolerated. Mefloquine, artesunate, and mefloquine-artesunate did not show an effect. Tribendimidine should be further investigated with large clinical trials.. Swiss National Science Foundation, University of Basel.

Topics: Adolescent; Animals; Anthelmintics; Artemisinins; Artesunate; Child; Drug Therapy, Combination; Female; Humans; Laos; Male; Mefloquine; Opisthorchiasis; Opisthorchis; Parasite Egg Count; Phenylenediamines; Praziquantel; Treatment Outcome

The food-borne liver fluke Opisthorchis felineus is an epidemiologically important species and the causative agent of opisthorchiasis across an extensive territory of Eurasia. For decades, treatment of opisthorchiasis has been based on praziquantel. Tribendimidine could be an alternative drug that has been successfully tested for Opisthorchis viverrini and Clonorchis sinensis infections. We aimed to assess tribendimidine effects in comparison with praziquantel in vivo and in vitro against the liver fluke Opisthorchis felineus.. The differences between WBR values after PZQ and TBN treatment were not significant, thus tribendimidine was as effective as praziquantel against O. felineus liver flukes. Given the broad-spectrum activity of tribendimidine and efficacy against O. felineus, this drug may be a promising candidate for the treatment of opisthorchiasis felinea and other liver fluke infections.

Topics: Animals; Anthelmintics; Cricetinae; Mesocricetus; Opisthorchiasis; Opisthorchis; Phenylenediamines; Praziquantel

Opisthorchiasis, caused by the liver fluke Opisthorchis viverrini, a food-borne trematode, is an important public health problem; however, only a single drug, praziquantel is available. We investigated tribendimidine-praziquantel combinations against O. viverrini in vitro and in vivo. The IC50 values of 0.16 μg/ml and 0.05 μg/ml were determined for praziquantel and tribendimidine, respectively, against adult O. viverrini in vitro. When O. viverrini was exposed to both drugs simultaneously (using a drug ratio based on the IC50 (1:3.2)) a synergistic effect was calculated (combination index (CI) at the IC50= 0.7). A similar result was observed when drug addition in vitro was spaced by the respective half-lives of the drugs (a CI of 0.78 at the IC50 for tribendimidine followed by praziquantel and a CI of 0.47 at the IC50 for praziquantel followed by tribendimidine). In vivo median-effect dose (ED50) values of 191 mg/kg and 147 mg/kg were calculated for praziquantel and tribendimidine, respectively. Low to moderate worm burden reductions (38-62%) were observed in O. viverrini infected hamsters when both drugs were administered simultaneously or on subsequent days, pointing to antagonistic effects in vivo. Further studies are necessary to understand the striking differences between the in vitro and in vivo observations using combinations of praziquantel and tribendimidine on O. viverrini.

Topics: Animals; Cricetinae; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Inhibitory Concentration 50; Male; Mesocricetus; Opisthorchiasis; Opisthorchis; Parasite Load; Phenylenediamines; Praziquantel; Survival Analysis

Topics: Adolescent; Animals; Anthelmintics; Child; Humans; Laos; Opisthorchiasis; Opisthorchis; Phenylenediamines; Randomized Controlled Trials as Topic; Treatment Outcome

The tegumental changes in adult Opisthorchis viverrini induced by tribendimidine were analyzed by scanning electron microscopy (SEM). We exposed O. viverrini to tribendimidine at a concentration of 10 microg/ml for 4 h. In addition, hamsters were treated with a single 400 mg/kg oral dose of tribendimidine and flukes were recovered from the bile ducts 24, 48, 72, and 96 h post-treatment. SEM analysis of the flukes incubated in vitro showed only mild damage of the tegument. Twenty-four hours post-treatment of hamsters, extensive disruption such as sloughing, furrowing, or blebbing of the tegument was evident, which did not increase in severity 48-72 h post-treatment. Ninety-six hours after tribendimidine administration, the majority of flukes had been expelled. A single 400 mg/kg oral dose of tribendimidine administered to O. viverrini-infected hamsters yielded a worm burden reduction of 63.0%. In conclusion, our experiments confirm that tribendimidine possesses interesting trematocidal properties, which warrant additional investigations and provide further data for subsequent clinical trials.

Topics: Animals; Anthelmintics; Cricetinae; Microscopy, Electron, Scanning; Opisthorchiasis; Opisthorchis; Parasitic Sensitivity Tests; Phenylenediamines; Treatment Outcome