Tribendimidine

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Jennifer Keiser - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections.
    Antimicrobial agents and chemotherapy, 2021
    Co-Authors: Janneke M. Brussee, Jean T. Coulibaly, Anna Neodo, Jessica D. Schulz, Marc Pfister, Jennifer Keiser
    Abstract:

    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, Emax 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.

  • Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection.
    Antimicrobial agents and chemotherapy, 2021
    Co-Authors: Janneke M. Brussee, Jean T. Coulibaly, Noemi Hiroshige, Anna Neodo, Marc Pfister, Jennifer Keiser
    Abstract:

    Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of Tribendimidine's primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether Tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected from 155 school-aged children and adolescents with hookworm infections, following Tribendimidine doses ranging from 100 to 400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets than with 50-mg tablets, while the extent of absorption remained unaffected. The identified Emax models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure led to marginal efficacy increase. Combination therapy should be considered, as a 12-fold-higher dose would be needed to achieve 95% ERRs and CRs >90% with Tribendimidine alone. Further studies are warranted to evaluate safety of higher Tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.

  • Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections.
    Antimicrobial agents and chemotherapy, 2019
    Co-Authors: Isabel Meister, Peter Odermatt, Jörg Huwyler, Somphou Sayasone, Melissa A. Penny, Fiona Vanobberghen, Joel Tarning, Piyanan Assawasuwannakit, Jennifer Keiser
    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.

  • Efficacy and Safety of Ascending Dosages of Tribendimidine Against Hookworm Infections in Children: A Randomized Controlled Trial.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018
    Co-Authors: Jean T. Coulibaly, Noemi Hiroshige, Yves K. N’gbesso, Jan Hattendorf, Jennifer Keiser
    Abstract:

    BACKGROUND The global strategy to control soil-transmitted helminthiasis is mainly focused on preventive chemotherapy with albendazole and mebendazole. We assessed the efficacy and safety of ascending Tribendimidine doses against hookworm infections in African school-aged children, key information for the development of Tribendimidine. METHODS We performed a single blind, randomized, controlled trial in Cote d'Ivoire between June and August 2017. Eligible participants were randomly assigned to placebo, 100, 200, or 400 mg Tribendimidine. Cure rates (CRs, primary outcome) and egg reduction rates (ERRs) were determined 14-21 days after treatment. Clinical symptoms were assessed before treatment and adverse events monitored 3 and 24 hours posttreatment. RESULTS CRs calculated for 130 children dose-dependently increased. The observed CRs were 20.6% (7/34), 21.2% (7/33), 38.7% (12/31), and 53.1% (17/32) for placebo, 100, 200, and 400 mg of Tribendimidine, respectively. The Emax model predicted a placebo corrected net effect of 34.3 percentage points (95% confidence interval [CI], 13.3-54.4) for the 400-mg Tribendimidine dose. The ERRs (geometric mean) were 30.6% (95% CI, -24.7 to 64.1), 65.4% (95% CI, 24.5-85.9), 82.1% (95% CI, 58.4-92.5) and 92.2% (95% CI, 81.0-97.1) for placebo, 100, 200, and 400 mg Tribendimidine, respectively. The Emax model predicted an ERR of 95% at 500 mg. Only mild adverse events and no abnormal biochemical parameters were observed. CONCLUSION A 400-mg dose of Tribendimidine yielded the highest efficacy and was well tolerated. Because children were mostly lightly infected, further investigations with Tribendimidine against moderate/heavy hookworm infection are needed. CLINICAL TRIALS REGISTRATION The trial is registered at www.isrctn.com number ISRCTN81391471.

  • In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine.
    Antimicrobial agents and chemotherapy, 2018
    Co-Authors: Anna Neodo, Jörg Huwyler, Jessica D. Schulz, Jennifer Keiser
    Abstract:

    ABSTRACT Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful in vitro and in vivo characterization is needed. The combination of Tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STHs and thus represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effects of combinations of ivermectin, oxantel pamoate, and Tribendimidine’s active metabolite deacylated amidantel (dADT) on cytochrome P450 (CYP450) metabolism were evaluated, followed by a pharmacokinetic analysis of Tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for Tribendimidine-oxantel pamoate at the CYP450 metabolism level, whereas a combination of Tribendimidine and ivermectin led to moderately increased CYP2D6 inhibition compared to ivermectin or Tribendimidine alone. Coadministration of Tribendimidine with ivermectin altered neither the time to maximum concentration of drug in plasma ( T max ) nor the elimination half-lives of dADT, the acetylated derivative of amidantel (adADT), and ivermectin. While the area under the concentration-versus-time curve (AUC) and maximum concentration of drug in plasma ( C max ) values of dADT, adADT, and ivermectin are reduced by coadministration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of Tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in humans.

Jürg Utzinger - One of the best experts on this subject based on the ideXlab platform.

  • Strongyloides ratti: In Vitro and In Vivo Activity of
    2013
    Co-Authors: Jennifer Keiser, Kai Thiemann, Yvette Endriss, Jürg Utzinger
    Abstract:

    Background: Strongyloidiasis is a truly neglected tropical disease, but its public health significance is far from being negligible. At present, only a few drugs are available for the treatment and control of strongyloidiasis. Methodology/Principal Findings: We investigated the activity of Tribendimidine against third-stage larvae (L 3) of Strongyloides ratti in vitro and against juvenile and adult stages of the parasite in vivo. S. ratti larvae incubated in PBS buffer containing 10–100 mg/ml Tribendimidine died within 24 hours. A single 50 mg/kg oral dose of Tribendimidine administered to rats infected with 1-day-old S. ratti showed no effect. The same dose administered to rats harboring a 2-day-old infection showed a moderate reduction of the intestinal parasite load. Three days post-exposure a significant reduction of the immature worm burden was found. Administration of Tribendimidine at doses of 50 mg/kg and above to rats harboring mature S. ratti resulted in a complete elimination of the larval and adult worm burden. For comparison, we also administered ivermectin at a single 0.5 mg/kg oral dose to rats infected with adult S. ratti and found a 90 % reduction of larvae and a 100 % reduction of adult worms. Conclusion/Significance: Tribendimidine exhibits activity against S. ratti in vitro and in vivo. The effect of Tribendimidine i

  • Mean (SE) fecal larvae output of 4 S. ratti-infected rats that remained untreated and S. ratti-infected rats treated with 50 mg/kg Tribendimidine either on day 1, 2 or 3 post-exposure.
    2013
    Co-Authors: Jennifer Keiser, Kai Thiemann, Yvette Endriss, Jürg Utzinger
    Abstract:

    Mean (SE) fecal larvae output of 4 S. ratti-infected rats that remained untreated and S. ratti-infected rats treated with 50 mg/kg Tribendimidine either on day 1, 2 or 3 post-exposure.

  • Mean (SE) fecal larvae output of 4 S. ratti-infected rats that remained untreated and 4 S. ratti-infected rats that were treated on day 5 post-exposure with either 0.5 mg/kg ivermectin, or either 50, 100 or 200 mg/kg Tribendimidine.
    2013
    Co-Authors: Jennifer Keiser, Kai Thiemann, Yvette Endriss, Jürg Utzinger
    Abstract:

    Mean (SE) fecal larvae output of 4 S. ratti-infected rats that remained untreated and 4 S. ratti-infected rats that were treated on day 5 post-exposure with either 0.5 mg/kg ivermectin, or either 50, 100 or 200 mg/kg Tribendimidine.

  • Efficacy and Safety of Tribendimidine against Clonorchis sinensis
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012
    Co-Authors: Men-bao Qian, Jürg Utzinger, Peiling Yap, Yi-chao Yang, Hai Liang, Zhi-hua Jiang, Yu-guang Tan, Hui Zhou, Xiao-nong Zhou
    Abstract:

    Background. Clonorchiasis is of considerable public health importance, particularly in the People's Republic of China (P.R. China), where most of the 15 million individuals infected with Clonorchis sinensis are currently concentrated. Praziquantel is the drug of choice, but Tribendimidine might be an alternative.Methods. We performed a randomized open-label trial in Guangxi, P.R. China to assess the efficacy and safety of 400 mg Tribendimidine once, 400 mg Tribendimidine daily for three days, and 75 mg/kg praziquantel in one day divided in three doses against parasitological confirmed C. sinensis infections. Cure and egg reduction rates were determined 3 weeks post-treatment using available case analysis. Clinical symptoms were documented at baseline, and adverse events were recorded and graded 3 and 24 h after each dose.Results. A total of 74 patients were included in the final analysis. Single-dose Tribendimidine achieved a cure rate of 44%, while cure rates of 58% and 56% were obtained for Tribendimidine administered for 3 days and praziquantel, respectively. High egg reduction rates (97.6-98.8%) were observed for all treatment regimens. Single-dose Tribendimidine was the best-tolerated treatment scheme. Patients treated with praziquantel experienced significantly more adverse events than Tribendimidine recipients (P >0.05).Conclusions. Tribendimidine has an efficacy comparable to praziquantel in the treatment of C. sinensis infection and resulted in fewer adverse events compared to praziquantel. Larger clinical trials are warranted among C. sinensis-infected patients to determine the potential of Tribendimidine against clonorchiasis and other helminthiases.Trial registration. Controlled-Trials.com, identifier: ISRCTN80829842.

  • Combination Chemotherapy against Clonorchis sinensis: Experiments with Artemether, Artesunate, OZ78, Praziquantel, and Tribendimidine in a Rat Model
    Antimicrobial agents and chemotherapy, 2009
    Co-Authors: Jennifer Keiser, Shuhua Xiao, Thomas J. Smith, Jürg Utzinger
    Abstract:

    Caused by the Chinese liver fluke Clonorchis sinensis, clonorchiasis is of growing public health importance. Treatment and control of the disease rely on a single drug, praziquantel, and little information regarding combination chemotherapy is available. Here, we evaluated the in vivo efficacy of praziquantel combined with artemether, artesunate, OZ78, and Tribendimidine, as well as an artesunate-Tribendimidine combination against C. sinensis, in a rat model. Data from previous experiments were included, and negative binomial regression analyses were carried out to determine dose-response relationships and to study the effect of drug combination. All drugs given in monotherapy were efficacious in killing the worms; doses of 16 and 70 mg/kg of body weight of artesunate, for example, reduced worm burden by 50% and 95%, respectively. Artemether and OZ78 (12.5 to 50 mg/kg) showed dose-dependent killing of worms but no significant drug interactions when given with 150 mg/kg praziquantel, suggesting independent additive effects. In contrast, artesunate and Tribendimidine (12.5 to 50 mg/kg) showed synergistic interactions with 150 mg/kg praziquantel. When low doses of 3.1 and 6.25 mg/kg OZ78 and artemether, respectively, were combined with praziquantel (150 mg/kg) an increased worm survival, above the level observed with praziquantel monotherapy, was noted. A similar antagonism was seen when praziquantel (75 mg/kg) was combined with several of the companion drugs at various doses. In conclusion, in vivo efficacy of praziquantel, the artemisinins, OZ78, and Tribendimidine against C. sinensis is confirmed, and combination chemotherapy with praziquantel produces synergistic and antagonistic effects depending on the doses administered. Further preclinical investigations are warranted.

Shuhua Xiao - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and safety of praziquantel, Tribendimidine and mebendazole in patients with co-infection of Clonorchis sinensis and other helminths.
    PLoS neglected tropical diseases, 2014
    Co-Authors: Bin Jiang, Shuhua Xiao, Ji-hui Duan, Shi-feng Zhuang, Yong-chun Liu, Shi-qiao Zhu, Li-ping Zhang, Haobing Zhang, Xiao-nong Zhou
    Abstract:

    Background Both Tribendimidine and mebendazole are broad-spectrum drugs for anti-intestinal nematodes. We aim to assess the efficacy and safety of Tribendimidine and mebendazole in patients with co-infection of Clonorchis sinensis and other helminths. Method We performed a randomized open-label trial in Qiyang, People's Republic of China. Eligible participants were randomly assigned to one of four groups: (i) a single dose of 400 mg Tribendimidine, (ii) 200 mg Tribendimidine twice daily, (iii) 75 mg/kg praziquantel divided in four doses within 2 days, and (iv) a single dose of 400 mg mebendazole. Cure rates and egg reduction rates were assessed, and adverse events were monitored after treatments. Uncured patients accepted the second treatment with the same drugs after the first treatment. Results 156 patients were eligible for the study. Results from the first treatment showed that the cure rates of single-dose Tribendimidine and praziquantel against C. sinensis were 50% and 56.8%, respectively; the single-dose Tribendimidine achieved the cure rate of 77.8% in the treatment for hookworm, which was significantly higher than that of praziquantel; Low cure rates were obtained in the treatment of single-dose Tribendimidine against Ascaris lumbricoides and Trichuris trichiura (28.6% and 23.1%). Results of the second treatment illustrated the cure rates of Tribendimidine and praziquantel against C. sinensis were 78.1% and 75%, respectively. Most adverse events were mild and transient. Adverse events caused by Tribendimidine were significantly less than praziquantel. Conclusion Single-dose Tribendimidine showed similar efficacy against C. sinensis as praziquantel with less adverse events, and achieved significantly higher cure rate in the treatment for hookworm than those of praziquantel and mebendazole. Low cure rates, which were still higher than other drugs, were obtained in the treatment of single-dose Tribendimidine against Ascaris lumbricoides and Trichuris trichiura. Trial Registration Controlled-Trials.com ISRCTN55086560

  • Efficacy and safety of praziquantel, Tribendimidine and mebendazole in patients with co-infection of Clonorchis sinensis and other helminths.
    Public Library of Science (PLoS), 2014
    Co-Authors: Bin Jiang, Shuhua Xiao, Ji-hui Duan, Shi-feng Zhuang, Yong-chun Liu, Shi-qiao Zhu, Li-ping Zhang, Haobing Zhang, Xiao-nong Zhou
    Abstract:

    Both Tribendimidine and mebendazole are broad-spectrum drugs for anti-intestinal nematodes. We aim to assess the efficacy and safety of Tribendimidine and mebendazole in patients with co-infection of Clonorchis sinensis and other helminths.We performed a randomized open-label trial in Qiyang, People's Republic of China. Eligible participants were randomly assigned to one of four groups: (i) a single dose of 400 mg Tribendimidine, (ii) 200 mg Tribendimidine twice daily, (iii) 75 mg/kg praziquantel divided in four doses within 2 days, and (iv) a single dose of 400 mg mebendazole. Cure rates and egg reduction rates were assessed, and adverse events were monitored after treatments. Uncured patients accepted the second treatment with the same drugs after the first treatment.156 patients were eligible for the study. Results from the first treatment showed that the cure rates of single-dose Tribendimidine and praziquantel against C. sinensis were 50% and 56.8%, respectively; the single-dose Tribendimidine achieved the cure rate of 77.8% in the treatment for hookworm, which was significantly higher than that of praziquantel; Low cure rates were obtained in the treatment of single-dose Tribendimidine against Ascaris lumbricoides and Trichuris trichiura (28.6% and 23.1%). Results of the second treatment illustrated the cure rates of Tribendimidine and praziquantel against C. sinensis were 78.1% and 75%, respectively. Most adverse events were mild and transient. Adverse events caused by Tribendimidine were significantly less than praziquantel.Single-dose Tribendimidine showed similar efficacy against C. sinensis as praziquantel with less adverse events, and achieved significantly higher cure rate in the treatment for hookworm than those of praziquantel and mebendazole. Low cure rates, which were still higher than other drugs, were obtained in the treatment of single-dose Tribendimidine against Ascaris lumbricoides and Trichuris trichiura.Controlled-Trials.com ISRCTN55086560

  • Negative binomial regression analysis of adverse events recorded within 48 h after drug administration in the first treatment.
    2014
    Co-Authors: Bin Jiang, Shuhua Xiao, Ji-hui Duan, Shi-feng Zhuang, Yong-chun Liu, Shi-qiao Zhu, Li-ping Zhang, Haobing Zhang, Xiao-nong Zhou
    Abstract:

    Group 1: the single-dose Tribendimidine vs praziquantel;Group 2: Tribendimidine 200 mg twice daily vs praziquantel.

  • Per-protocol analysis of prevalence and cure rates of praziquantel, Tribendimidine and mebendazole in patients co-infected with C. sinensis and other helminths at follow-up, with Kato-Katz smear technique.
    2014
    Co-Authors: Bin Jiang, Shuhua Xiao, Ji-hui Duan, Shi-feng Zhuang, Yong-chun Liu, Shi-qiao Zhu, Li-ping Zhang, Haobing Zhang, Xiao-nong Zhou
    Abstract:

    Per-protocol analysis of prevalence and cure rates of praziquantel, Tribendimidine and mebendazole in patients co-infected with C. sinensis and other helminths at follow-up, with Kato-Katz smear technique.

  • Per-protocol analysis of prevalence and CRs of praziquantel and Tribendimidine in patients infected with C. sinensis at follow-up in the second treatment.
    2014
    Co-Authors: Bin Jiang, Shuhua Xiao, Ji-hui Duan, Shi-feng Zhuang, Yong-chun Liu, Shi-qiao Zhu, Li-ping Zhang, Haobing Zhang, Xiao-nong Zhou
    Abstract:

    Per-protocol analysis of prevalence and CRs of praziquantel and Tribendimidine in patients infected with C. sinensis at follow-up in the second treatment.

Peter Odermatt - One of the best experts on this subject based on the ideXlab platform.

  • Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections.
    Antimicrobial agents and chemotherapy, 2019
    Co-Authors: Isabel Meister, Peter Odermatt, Jörg Huwyler, Somphou Sayasone, Melissa A. Penny, Fiona Vanobberghen, Joel Tarning, Piyanan Assawasuwannakit, Jennifer Keiser
    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.

  • Efficacy and safety of Tribendimidine versus praziquantel against Opisthorchis viverrini in Laos: an open-label, randomised, non-inferiority, phase 2 trial.
    The Lancet. Infectious diseases, 2017
    Co-Authors: Somphou Sayasone, Jennifer Keiser, Jan Hattendorf, Isabel Meister, Youthanavanh Vonghachack, Syda Xayavong, Kanpaseuth Senggnam, Khampheng Phongluxa, Peter Odermatt
    Abstract:

    Summary Background 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. Method 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. Findings 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 Interpretation 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. Funding Joint Global Health Trials scheme from the Wellcome Trust, Department for International Development, and Medical Research Council.

  • Single-Ascending-Dose Pharmacokinetic Study of Tribendimidine in Opisthorchis viverrini-Infected Patients
    Antimicrobial agents and chemotherapy, 2016
    Co-Authors: Urs Duthaler, Peter Odermatt, Jörg Huwyler, Somphou Sayasone, Fiona Vanobbergen, Melissa A. Penny, Jennifer Keiser
    Abstract:

    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.).

  • Population pharmacokinetic modeling of Tribendimidine metabolites in Opisthorchis viverrini-infected adults
    Antimicrobial agents and chemotherapy, 2016
    Co-Authors: Fiona Vanobberghen, Jennifer Keiser, Peter Odermatt, Somphou Sayasone, Urs Duthaler, Melissa A. Penny, Joel Tarning
    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.).

  • Efficacy and safety of Tribendimidine against Opisthorchis viverrini : two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials
    The Lancet. Infectious diseases, 2016
    Co-Authors: Somphou Sayasone, Peter Odermatt, Jan Hattendorf, Youthanavanh Vonghachack, Syda Xayavong, Kanpaseuth Senggnam, Kongsap Akkhavong, Urs Duthaler, Jennifer Keiser
    Abstract:

    Summary Background 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. Methods 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 E max models. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN96948551. Findings 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 E max 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 E max 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%]). Interpretation 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. Funding Department for International Development, Medical Research Council, Wellcome Trust Joint Global Health Trials Scheme.

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  • Effect of single-dose oral artemether and Tribendimidine on the tegument of adult Clonorchis sinensis in rats
    Parasitology research, 2008
    Co-Authors: Shuhua Xiao, Marcel Tanner, Jennifer Keiser, Jian Xue, Gianni Morson, Jürg Utzinger
    Abstract:

    The tegument of trematodes plays a key role in nutrient absorption, exerts secretory functions, protects the parasite against the immune system of the host, and is a target for anti-trematocidal drugs. We performed a temporal examination of tegumental changes following artemether and Tribendimidine administration on adult Clonorchis sinensis in rats using scanning electron microscopy. Rats infected with C. sinensis for 6 weeks were treated orally with a single dose of artemether (150 mg/kg) or Tribendimidine (300 mg/kg). Worms were collected between 8 h and 7 days (artemether) and between 4 h and 2 days post-treatment (Tribendimidine). Worms recovered from untreated rats served as controls. Eight hours after artemether administration, the tegument of C. sinensis was extensively disrupted, including severe swelling, fusion and vacuolization, and the suckers were damaged. Four hours after administration of Tribendimidine, C. sinensis worms showed extensive tegumental alterations, characterized by massive sloughing, and the suckers were damaged. Interestingly, the severity of tegumental changes did not progress further with time. Our results show that both artemether and Tribendimidine rapidly disrupt the tegument and damage the suckers of adult C. sinensis. The subtle differences in tegumental changes induced by artemether and Tribendimidine might indicate different mechanisms of action of these drugs against C. sinensis.

  • Effect of Tribendimidine, artesunate, artemether and praziquantel, administered intragastrically at single, multiple or combined doses, to rats infected with Clonorchis sinensis
    Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases, 2008
    Co-Authors: Shuhua Xiao, Yong-nian Zhang, Marcel Tanner, Jennifer Keiser, Jürg Utzinger, Jian Xue, Hui-qin Qiang, Xiao-yun Liu
    Abstract:

    OBJECTIVE: To assess the efficacy of single, multiple or combined oral doses of Tribendimidine, artesunate, artemether and praziquantel against Clonorchis sinensis in rats. METHODS: A total of 147 rats, each infected with 50 C. sinensis metacercariae, were used in experimental chemotherapy. All the drugs used were administered intragastrically 42-44 d after infection. (1) Sixty infected rats were randomly divided into 11 groups (4-5 rats per group) and the following drug dose-schedules were applied, i.e. under the same total dose Tribendimidine or praziquantel was given at a single dose of 150 mg/kg, or given at smaller divided doses of 75 mg/kg (qd for 2 d), 50 mg/kg (qd for 3 d), 25 mg/kg (tid for 2 d); artesunate or artemether was given at a single dose of 75 mg/kg, or given a half dose of 37.5 mg/kg daily for 2 days. (2) Eighty-seven infected rats were randomly divided into 15 groups (4-6 rats per group) for combined treatment with the following drug administration regimens, i.e. artesunate or artemether 30 mg/kg plus praziquantel 150 mg/kg or Tribendimidine 50 mg/kg and 75 mg/kg, respectively; Tribendimidine 50 mg/kg plus praziquantel 150 mg/kg; Tribendimidine 75 mg/kg plus praziquantel 187.5 mg/kg. A single dose of each drug mentioned above was also involved. Untreated C. sinensis-infected rats served as control. Rats were killed 14 days post-treatment, worms recovered from the bile duct and the liver tissue, mean worm burden reduction calculated and mean worm burden compared between the groups using non-parametric method (Mann-Whitney test). RESULTS: Rats infected with C. sinensis and treated at a single 150 mg/kg dose of either Tribendimidine or praziquantel resulted in a worm reduction of 57.2% and 63.8%, respectively. Whilst administration of Tribendimidine at smaller but multiple doses given within 2-3 days at the same total dosage resulted in a slightly higher worm reduction (77.1%-79.4%), the opposite trend was observed for praziquantel (50.6%-54.2%). However, for both Tribendimidine and praziquantel, the difference of mean worm burden lacked statistical significance between single and multiple doses. Infected rats administered either artesunate or artemether at a single dose of 75 mg/kg or a daily dose of 37.5 mg/kg for 2 days, the worm reduction was 100% and 90.4%-98.5%, respectively. Combined treatment with low doses of Tribendimidine (50 mg/kg or 75 mg/kg) plus praziquantel (150 mg/kg or 187.5 mg/kg) resulted in a worm reduction of 74.9%-100%, which were higher than those of 26.9%-79.6% obtained from a single dose of each drug used. High worm reduction of 74.4%-97.9% was also observed when administering a low dose of artesunate or artemether (30 mg/kg) plus a low dose of Tribendimidine (50 mg/kg or 75 mg/kg) or praziquantel (150 mg/kg). Mean worm reduction of 24.8%-79.6% were seen when drugs used at single doses. CONCLUSION: The investigation confirmed that Tribendimidine, artesunate, artemether-and praziquantel are all efficacious against C. sinensis, and that drug combination acts synergistically.

  • artemether artesunate praziquantel and Tribendimidine administered singly at different dosages against clonorchis sinensis a comparative in vivo study
    Acta Tropica, 2008
    Co-Authors: Shuhua Xiao, Marcel Tanner, Jennifer Keiser, Jürg Utzinger, Xue Jian, Zhang Yongnian, Qiang Huiqiang
    Abstract:

    We comparatively assessed the in vivo efficacy of artemether, artesunate, praziquantel and Tribendimidine against different stages of Clonorchis sinensis. Rats were infected with 40-50 C. sinensis metacercariae, and drugs were administered singly by the oral route at different dosages. Rats were dissected 2-4 weeks post-treatment and C. sinensis trematodes were removed from the liver and bile ducts and counted. We used a negative binomial regression model to test the effect of drug and dosage in terms of worm burden reduction. Single 150 mg/kg oral doses of artesunate, artemether, Tribendimidine and praziquantel, administered to rats infected with adult C. sinensis, resulted in mean worm burden reductions of 100, 100, 89.5 and 80.7%, respectively (all P<0.001). Halving the dose to 75 mg/kg still resulted in highly significant worm burden reductions for artesunate, artemether and Tribendimidine (71.4-100%), but not for praziquantel (20.7%). In the juvenile infection model, a single 150 mg/kg oral dose of Tribendimidine and praziquantel resulted in mean worm burden reductions of 99.1 and 90.0%, respectively, whereas considerably lower reductions were observed for artemether (59.2%) and artesunate (57.6%) when used at the same single dose. The in vivo results presented here with the artemisinins and Tribendimidine provide further data for clinical investigations to assess the safety and efficacy of these drugs in clonorchiasis patients.

  • artemether and Tribendimidine lack activity in experimental treatment of paragonimus westermani in the dog
    Parasitology Research, 2008
    Co-Authors: Jürg Utzinger, Yong-nian Zhang, Marcel Tanner, Jennifer Keiser, Shuhua Xiao
    Abstract:

    Artemether and Tribendimidine are active against several trematode species, but no data are available regarding the lung fluke Paragonimus westermani. We infected six dogs with 100 P. westermani metacercariae each. At day 103 post-infection, four dogs were treated orally for 3 days with either artemether (total dose, 66.7 and 75 mg/kg) or Tribendimidine (total dose, 100 mg/kg). The remaining dogs were left untreated and served as control. Sixteen days after the final dosing, dogs were killed, and P. westermani flukes were recovered from the lungs and counted. Neither artemether nor Tribendimidine showed activity against P. westermani at this dose regimen in dogs.

  • Artemether, artesunate, praziquantel and Tribendimidine administered singly at different dosages against Clonorchis sinensis : a comparative in vivo study
    Acta tropica, 2008
    Co-Authors: Shuhua Xiao, Marcel Tanner, Jennifer Keiser, Jürg Utzinger, Xue Jian, Zhang Yong-nian, Qiang Hui-qiang
    Abstract:

    We comparatively assessed the in vivo efficacy of artemether, artesunate, praziquantel and Tribendimidine against different stages of Clonorchis sinensis. Rats were infected with 40-50 C. sinensis metacercariae, and drugs were administered singly by the oral route at different dosages. Rats were dissected 2-4 weeks post-treatment and C. sinensis trematodes were removed from the liver and bile ducts and counted. We used a negative binomial regression model to test the effect of drug and dosage in terms of worm burden reduction. Single 150 mg/kg oral doses of artesunate, artemether, Tribendimidine and praziquantel, administered to rats infected with adult C. sinensis, resulted in mean worm burden reductions of 100, 100, 89.5 and 80.7%, respectively (all P