Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection.

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.

Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections.

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.

Efficacy and Safety of Ascending Dosages of Tribendimidine Against Hookworm Infections in Children: A Randomized Controlled Trial.

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 Côte 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.

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

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.

In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine.

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 (Tmax) 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 (Cmax) 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.

Pharmacokinetics of a Pediatric Tribendimidine Dose-Finding Study To Treat Hookworm Infection in African Children.

Tribendimidine is a broad-spectrum anthelminthic available in China, which is currently being pursued for U.S. Food and Drug Administration approval for soil-transmitted helminth infections. Pharmacokinetic (PK) studies with tribendimidine in children, the main target group for treatment programs, have not been conducted to date. In the framework of a dose-ranging study in hookworm-infected school-aged children in Côte d'Ivoire, children were treated with either 100, 200, or 400 mg tribendimidine. Dried blood spot samples were collected up to 22 h after treatment. The active metabolite, deacetylated amidantel (dADT) and its metabolite acylated dADT (adADT) were quantified using liquid chromatography tandem mass spectrometry. PK parameters were calculated using a noncompartmental model, and univariate logistic regression was applied using maximal blood concentrations (Cmax) and area under the blood concentration-time curve for 0 to 22 h (AUC0-22) as predictors of drug efficacy. Dried blood spot samples of 101 children were analyzed. We observed a less than proportional and proportional exposure in dADT's median Cmax and AUC0-22, respectively, following administration of 100 mg (Cmax = 853 ng/ml; AUC0-22 = 3,019 h · ng/ml) and 400 mg (Cmax = 2,275 ng/ml; AUC0-22 = 12,530 h · ng/ml) tribendimidine. There were large, dose-independent variations in the time to Cmax (Tmax) and ratios of dADT to adADT. We did not detect an influence of Cmax or AUC0-22 of dADT or adADT on drug efficacy or adverse events. Since our study population was bearing hookworm infection of mainly low intensity, additional studies with heavy intensity infections might be required to confirm this observation.

Carbon-14 labelled tribendimidine, a broad-spectrum anthelmintic drug.

The preparation of [(14) C]tribendimidine, a broad-spectrum anthelmintic agent related to amidantel, and its use during excretion and metabolism studies in the rat are described in this paper.

The pipeline for drugs for control and elimination of neglected tropical diseases: 2. Oral anti-infective drugs and drug combinations for off-label use.

In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.

Swiss-Chinese Cooperation in Tropical Medicine: The Role of Professor Marcel Tanner.

This paper is in honour of Professor Marcel Tanner, President of the Swiss Academies of Arts and Sciences, and former Director of the Swiss Tropical and Public Health Institute (Swiss TPH), in Basel, Switzerland. In the 30 plus years since his first visit to China in 1989, Professor Tanner has tirelessly promoted research collaboration between Switzerland and China on health and tropical diseases through international meetings, scholar exchange, and training of young scientists. As a contribution to Professor Tanner's life's work of collaboration with Chinese scientists, we summarize here ideas conceived, work initiated and major outcomes. His approach, embodied in his flowery expression: "Alps and Himalayas never meet, but Swiss and Chinese can", marked the occasion in 2013 when Xinhua Co., Ltd., a pharmaceutical company in Shandong of China, agreed to produce tribendimidine, a new remedy for tropical helminth infections, that was the fruit of long-term research by scientists at the Swiss TPH in Basel, and National Institute of Parasitic Diseases (NIPD) in Shanghai. This was neither the first nor the last of Professor Tanner's forceful, yet diplomatic influence, and we follow in his footprints when continuing in Swiss-Chinese cooperation in tropical medicine.

Metabolome alterations in Clonorchis sinensis after treatment with tribendimidine and praziquante in vivo.

Tribendimidine (TBD) is a broad-spectrum anthelmintic drug that is also significantly effective in treating clonorchiasis. In this study, the altered metabolomes of Clonorchis sinensis (C. sinensis) in rats after TBD administration were quantified by using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) to explore the possible active sites of TBD against clonorchiasis through altered metabolites and metabolic pathway analysis, and the results are expected to provide a target for the future design of anti-Clonorchis sinensis drugs. The worm burden reduction rate and scanning electron microscopy demonstrated that praziquantel (PZQ, positive control drug) and TBD had significant effects on C. sinensis in rats after treatment at a single dose of 200 mg/kg for 24 h. For the MS-based metabolomic analysis, a total of 173 standard metabolites (126 amino acids, 10 phospholipids and 37 fatty acids) were utilized as a reference metabolite database for metabolome identification. In total, 32 amino acids, 71 phospholipids and 27 fatty acids were detected in the C. sinensis of each group. Among these metabolites, 10 amino acids were significantly decreased in both drug-treated groups. Four lysophosphatidyl cholines (LPCs), six lysophosphatidyl ethanolamines (LPEs) and one phosphatidyl inositol (PI) were significantly increased after treatment with TBD. There were no significant changes in fatty acids among the control group and the two drug-treated groups. The results indicated that TBD administration caused a decrease in amino acids involved in the metabolic pathways of energy consumption and an increase in lysophospholipids, which are the hydrolysis products of phospholipase2 (PLA2) in the phospholipid metabolic pathways. The increased lysophospholipid content can destroy the cell membrane, increase membrane permeability, and even cause exposure to internal antigens that can be attacked by host antibodies. Perhaps the destroyed membrane, the exposed internal antigens and the consumed energy are the cause of the damage and death of C. sinensis after TBD administration. This is an interesting problem that can be examined in future research.

A study of tribendimidine effects in vitro and in vivo on the liver fluke Opisthorchis felineus.

BACKGROUND: 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. RESULTS: In this study we (i) calculated half-maximal inhibitory concentrations (IC50) by motility tests against O. felineus adults and newly excysted metacercarie after tribendimidine treatment in vitro; (ii) determined whether tribendimidine and PZQ effects on adult liver flukes are dependent on or mediated by white blood cells; and (iii) tested in vivo the anthelmintic activity of tribendimidine on juvenile and adult worms. We found that the efficiency of tribendimidine in vitro was similar (IC50 = 0.23 µM for newly excysted metacercariae and 0.19 µM for adult worms) to that of praziquantel (IC50 0.98 µM for newly excysted metacercariae and 0.47 µM for adult worms). The treatment of adult worms in vivo with praziquantel or tribendimidine at 400 mg/kg resulted in a 76% and 77.2% reduction, respectively, in the worm burden during chronic infection. CONCLUSIONS: 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.

Development and application of anthelminthic drugs in China.

China was once a country plagued by parasitic diseases. At the beginning of the founding of the People's Republic of China, nearly 80% of the population suffered from parasitic diseases because of poverty and poor sanitary conditions. After nearly 70 years of development, China has made remarkable achievements in the prevention and control of parasitic diseases, and the prevalence of parasitic diseases has been greatly reduced. In addition to organizational leadership from the government and various preventive measures, drug treatment and drug research & development are important and irreplaceable links in prevention and control work. Since the 1950s, China has begun to introduce, produce and imitate antiparasitic drugs from abroad, such as santonin, benzimidazole, and praziquantel. Chinese scientists have also contributed to the optimization of production techniques, improvements in drug formulation, the application in the clinic and the mechanisms of actions of generic drugs. At the same time, China has independently developed tribendimidine (TrBD, a broad spectrum anthelminthic), and its anthelminthic spectrum has been comprehensively studied. It is active against almost 20 parasites, is especially superior to benzimidazoles against Necator americanus, and surpasses the effectiveness of praziquantel against Clonorchis sinensis. In the treatment of tapeworm disease, the traditional Chinese medicines pumpkin seeds and betel nuts have good curative effects for taeniasis. Chinese scientists have explored the action modes and clinical administration methods of pumpkin seeds and betel nuts, which is still the main clinical regimen for the disease. This paper reviews the history and progress of the study of anthelmintics in intestinal helminth infections since the founding of the People's Republic of China and aiming to support clinicians and drug researchers in China and other countries.

LC-MS/MS method for the determination of two metabolites of tribendimidine, deacylated amidantel and its acetylated metabolite in plasma, blood and dried blood spots.

Tribendimidine has emerged as potential alternative to praziquantel in the treatment of Opisthorchis viverrini infections. To support its clinical development program, a quantitative high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed for tribendimidine's degradation product deacylated amidantel (dADT) and its acetylated metabolite adADT. Analytical sample preparation included protein precipitation for blood and plasma, and direct processing of dried blood spots (DBS). The analytes were detected by multiple reaction monitoring with electrospray ionization in the positive mode (dADT: 178.3→133.1 m/z, adADT: 220.4→175.1 m/z, tribendimidine 294.3→249.0 m/z). A pentafluorophenyl (PFP) phase Kinetex analytical column (2.6 µm, 100 Å, 50 mm × 4.6 mm) with a 6 min lasting mobile phase gradient program of ammonium acetate and acetonitrile was applied. The method was validated with respect to precision, accuracy, linearity, sensitivity, and selectivity. The analytical range in plasma and blood was 1-1000 ng/ml and in DBS 10-2000 ng/ml (R(2)>0.99). Recoveries determined using four different human blood batches were in the range of 70-90%. Inter- and intra-assay accuracy and precision deviations were at least ≤12.2%. dADT and adADT were stable within the autosampler for 72 h (10°C), for 4 h at room temperature, for 3 month at -80°C, and after three freeze and thaw cycles. DBS samples should be stored at -20°C. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be applied for pharmacokinetic studies with tribendimidine.

Anthelmintics: The best way to predict the future is to create it.

'The best way to predict the future is to create it.' When we look at drugs that are used to control parasites, we see that new knowledge has been created (discovered) about their modes of action. This knowledge will allow us to predict combinations of drugs which can be used together rationally to increase the spectrum of action and to slow the development of anthelmintic resistance. In this paper we comment on some recent observations of ours on the modes of action of emodepside, diethylcarbamazine and tribendimidine. Emodepside increases the activation of a SLO-1 K(+) current inhibiting movement, and diethylcarbamazine has a synergistic effect on the effect of emodepside on the SLO-1 K(+) current, increasing the size of the response. The combination may be considered for further testing for therapeutic use. Tribendimidine is a selective cholinergic nematode B-subtype nAChR agonist, producing muscle depolarization and contraction. It has different subtype selectivity to levamisole and may be effective in the presence of some types of levamisole resistance. The new information about the modes of action may aid the design of rational drug combinations designed to slow the development of resistance or increase the spectrum of action.