There is a worldwide upscale in mass drug administration (MDA) programs to control the morbidity caused by soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura and hookworm. Although anthelminthic drugs which are used for MDA are supplied by two pharmaceutical companies through donation, there is a wide range of brands available on local markets for which the efficacy against STHs and quality remain poorly explored. In the present study, we evaluated the drug efficacy and quality of two albendazole brands (Bendex and Ovis) available on the local market in Ethiopia. A randomized clinical trial was conducted according to the World Health Organization (WHO) guidelines to assess drug efficacy, by means of egg reduction rate (ERR), of Bendex and Ovis against STH infections in school children in Jimma, Ethiopia. In addition, the chemical and physicochemical quality of the drugs was assessed according to the United States and European Pharmacopoeia, encompassing mass uniformity of the tablets, amount of active compound and dissolution profile. Both drugs were highly efficacious against A. lumbricoides (>97%), but showed poor efficacy against T. trichiura (~20%). For hookworms, Ovis was significantly (p < 0. 05) more efficacious compared to Bendex (98. 1% vs. 88. 7%). Assessment of the physicochemical quality of the drugs revealed a significant difference in dissolution profile, with Bendex having a slower dissolution than Ovis. The study revealed that differences in efficacy between the two brands of albendazole (ABZ) tablets against hookworm are linked to the differences in the in-vitro drug release profile. Differences in uptake and metabolism of this benzimidazole drug among different helminth species may explain that this efficacy difference was only observed in hookworms and not in the two other species. The results of the present study underscore the importance of assessing the chemical and physicochemical quality of drugs before conducting efficacy assessment in any clinical trials to ensure appropriate therapeutic efficacy and to exclude poor drug quality as a factor of reduced drug efficacy other than anthelminthic resistance. Overall, this paper demonstrates that “all medicines are not created equal”.
Currently, there is a worldwide upscale in the implementation of programs to control and to eliminate a selection of 10 neglected tropical diseases [1,2]. Among these, soil-transmitted helminthiasis causes the highest burden on public health. It is estimated that more than 1. 4 billion people were infected with at least one of the four STH species: the roundworm Ascaris lumbricoides, the whipworm Trichuris trichiura and the two hookworm species Necator americanus and Ancylostoma duodenale, resulting in a global burden of approximately 5. 2 million disability-adjusted life years (DALYs) (20% of the total number of DALYs attributable to neglected tropical diseases) [3,4]. To control the morbidity caused by STH, mass drug administration (MDA) of a single oral dose of a benzimidazole anthelminthic drug (ABZ or MEB) is recommended in communities where the prevalence of any STH exceeds 20% [5]. To date, major pharmaceutical companies such as GlaxoSmithKline (ABZ, Zentel) and Johnson and Johnson (MEB, Vermox) are donating these medicines to WHO, which subsequently distribute these medicines to its recipient countries. In Ethiopia, the donated medicines are made available for the patients through government hospitals and health centers. The therapeutic efficacy of these products at the WHO-recommended dosages (i. e. single dose of 400 mg ABZ or 500 mg MEB) has recently been evaluated in two consecutive multinational trials [6,7]. These trials showed that the therapeutic efficacy measured in terms of egg reduction rate (ERR), varied both between drugs and STH species: both drugs showing high efficacy against A. lumbricoides (> 98%) and poor efficacy against T. trichiura (~64%), and ABZ being more efficacious against hookworms compared to mebendazole (96% vs. 80%). In addition to these two donated brands, there is a wide range of other brands available on local markets of STH endemic countries, which are often more accessible to the local people, but for which the efficacy or quality remain poorly explored [8]. The latter is particularly important in countries where resources are limited to monitor the quality of drugs, and hence in which prevalence of substandard, falsified or illegal drugs is substantial [9–14]. Although the quality of medicines has a direct influence on therapeutic efficacy, this remains poorly studied for benzimidazole anthelminthic drugs against STH infections. Therefore, we assessed both the efficacy and quality of two brands of ABZ commonly administered for the treatment of individual STHs in Ethiopia, namely Bendex and Ovis.
The study protocol was approved by the Ethical Committees of Jimma University (Ethiopia) (reference no RPGC/282/2014) and of the Faculty of Medicine, Ghent University (Belgium) (ref. no 2013/1114; B670201319330). The study is registered under clinicaltrial. gov identifier number NCT02420574 (https: //clinicaltrials. gov/ct2/show/NCT02420574? term=NCT02420574&rank=1). The school authorities, teachers, parents, and the children were informed about the purpose and procedures of the study. The written consent form was prepared in two commonly used local languages (Afaan Oromo and Amharic) and handed over to the children’s parents/guardians after explaining the aim, confidentiality and entire procedure of the clinical trial. Only those children (i) who were willing to participate and (ii) whose parents or guardians signed the written informed consent form were included in the study. Moreover, an additional separate written informed consent form for children older than 12 years was prepared, read and handed over to them and their additional written informed consent obtained (S1 Checklist). Samples of the two ABZ brands (Bendex, India, CIPLA Ltd, batch no: x21253 and Ovis, Korea, DaeHWa Pharmaceuticals, batch no: 2020) with a label claim of 400 mg/tablet and expiry date of November 2015 were purchased from private community pharmacy in Jimma town, Ethiopia. The quality of the drugs was evaluated by investigating three efficacy-critical quality attributes: (i) the mass uniformity, (ii) the amount of the active compound, and (iii) the dissolution of the tablets.
In total, 679 subjects were recruited of which 418 subjects were enrolled and randomized across the two brands of ABZ (nBendex = nOvis = 209). T. trichiura was the most prevalent (69. 4%), followed by A. lumbricoides (53. 6%). Hookworm infections were found in 28. 2% of the subjects. In total 388 subjects completed the trial (nBendex = 197; nOvis = 191), resulting in a compliance rate of more than 90%. There was no significant difference in mean age (Bendex: 10. 3 years vs. Ovis: 10. 3 years, p = 1. 00), sex ratio (Bendex: 1. 07 vs. Ovis: 0. 87, p = 1. 00) and mean fecal egg count (FEC) (A. lumbricoides: Bendex: 8,706 egg per gram of feces (EPG) vs. Ovis: 7,935, p = 0. 69; T. trichiura: Bendex: 909 EPG vs. Ovis: 769, p = 0. 45; hookworm: Bendex: 355 EPG vs. Ovis: 335, p = 0. 79) between the two arms at baseline. Both brands showed high efficacy against A. lumbricoides (Bendex: 98. 7% vs. Ovis: 97. 8%, p = 0. 64), and poor efficacy against T. trichiura (Bendex: 24. 4% vs. Ovis: 20. 4%, p = 0. 81). For hookworm infections, Ovis was more efficacious than Bendex, though the difference was marginally significant (Bendex: 88. 7% vs. Ovis: 98. 1%, p = 0. 05). Based on the WHO criteria to classify the efficacy of anthelminthic drugs (Table 1), both brands had satisfactory and reduced efficacy against A. lumbricoides and T. trichiura, respectively. For hookworms, Ovis had a satisfactory efficacy, whereas Bendex had a doubtful efficacy. A pairwise comparison of baseline parameters and drug efficacy between Bendex and Ovis are presented in S1 Table.
Assessing the quality and in-vivo efficacy differences between different brands of ABZ tablets are very critical to avoid indiscriminate use of different brands that could influence intended therapeutic outcomes. In the present study, we evaluated comparative in-vivo efficacy and in-vitro quality of two commonly available brands of ABZ tablets (Bendex and Ovis) that are used to treat STH infection. The in-vivo efficacy results of two brands of ABZ against A. lumbricoides and T. trichiura determined in terms of ERR, suggest the susceptibility difference between the two STHs. Therapeutic efficacy of antihelmnthics can be influenced by various factors such as infection intensity and susceptibility of parasites. Thus the reduced efficacy of both brands against T. trichiura observed in the present study could be due to high level of infection intensity [17] and/or genetic modification of beta-tubulin gene [26,27]. Since concentration of API at the target site of the parasites could be low due to metabolism and/or limited absorption of the drug by the parasite [28,29], the reduced efficacy of both brands against T. trichiura might also be associated with the pharmacokinetics of ABZ in the parasite. The reduced efficacy of the two brands against T. trichiura observed in the present study is comparable to the results reported in the previous studies [6,17]. The present finding, i. e. high prevalence of T. trichiura among other STHs in the study area together with the reduced efficacy results in ERR observed for single dose of ABZ 400 mg tablets, is supported by various literature findings [30–33]. This emphasizes the urgent need for alternative drugs and/or development of novel anthelmintic drugs to tackle this efficacy problem. Medicines quality is a critical factor that could affect efficacy of drugs against parasites [34] and for biopharmaceutical classification system (BCS) class II [35] drugs like ABZ that have low solubility and high permeability, dissolution is the rate-limiting step for drug absorption. Hence, in-vivo/in-vitro correlation between blood concentration profile and dissolution profile may be expected. Since the bioavailability of ABZ to the host is very low and also shows variability between individuals [36], a decreased dissolution could significantly worsen bioavailability, which in turn diminishes in-vivo efficacy of both the parent drug and therapeutically active metabolite (ABZ sulphoxide). Moreover, the capacity of anthelminthics to dissolve appropriately is an essential characteristic that allows proper drug uptake by the parasites and therefore assures the appropriate drug efficacy. Therefore, the four times decreased dissolution of Bendex compared to Ovis (Fig 2) which could influence both local and systemic concentration is a plausible explanation for the efficacy difference between the two brands against hookworms, which are blood sucking parasites. Previous studies already indicated the differences in uptake and metabolism of benzimidazole drugs among different helminth species [28,29], which may explain that the efficacy difference between the two brands was only observed against hookworms. Though mass uniformity and content of API per tablet are critical quality attributes that could influence efficacy, comparable quality of both brands with respect to mass uniformity and ABZ content observed in the present study (Table 2) explain the efficacy difference between the two brands against hookworms is not associated with mass uniformity and content of API. Considering a single point dissolution specification for ABZ tablets as described in the USP, i. e. Q ≥ 80% dissolved in 30 min [22], there is a statistically significant (p ≤ 0. 05) difference observed between Bendex (Q = 20%) and Ovis (Q = 85%) (Fig 2). Also, the area under the dissolution curve between defined time points (0,15,30,45 min) or DE quantifies the poor in-vitro dissolution of Bendex. While Ovis thus complied to the USP dissolution specifications, Bendex on the contrary did not. Although an undesirable polymorphic solid state of albendazole could be one of the reasons for the difference in dissolution behavior of API [37–39], the IR spectra (Figs 3 and 4) of Bendex and Ovis showed no significant difference between the two brands. The absence of significant observed shifts in IR-absorption indicates the similarity in polymorphic form of ABZ in both brands. Thus, the significant difference in dissolution observed between the two brands could not be associated with different polymorphic forms of ABZ. Whatever the reason of dissolution difference is, e. g. excipient and processing manufacturing conditions and stability, the poor dissolution behavior of Bendex observed in the present study is in accordance with the previous reports in which 41 samples out of 72 samples of solid oral dosage forms including ABZ tablets, different generic formulations of albendazole tablets and carbamazepine immediate-release products did not comply with the established acceptance criteria [40–42]. In general, it is important to note that quality of medicines could be one of the factors influencing outcomes of clinical trials. For instance, literature indicates the association of poor quality of locally manufactured antimalarial drugs: Sulfadoxine-Pyrimethamine with clinical failure of malaria treatment in Pakistan [43]. Therefore, the results of the present study and a recent report by Newton and his colleagues [44] point to the requirement of guidelines for quality assurance of medicines used in clinical trials. Subjects lost at follow-up per STH species were the limitations of this study. In conclusion, this study demonstrated that the two investigated brands of ABZ tablets are efficacious against A. lumbricoides and hookworm while both brands had reduced efficacy against T. trichiura. However, there was a significant difference between the two brands of ABZ against hookworm. While both brands showed comparable tablet mass uniformity and albendazole content, the in-vitro dissolution release profile between the two brands was significantly different, explaining the clinical efficacy difference observed. The results of the present study underscore the importance of assessing the chemical and physicochemical quality of drugs before conducting efficacy assessment in clinical trials to ensure appropriate therapeutic efficacy and to exclude poor drug quality as a factor of reduced drug efficacy other than anthelminthic resistance. Our in-vivo efficacy study clearly indicates the importance of appropriate quality medicines.
Soil-transmitted helminths (STHs) infect millions of children worldwide. To fight STH, large-scale de-worming programs are implemented in which anthelmintic drugs (either albendazole (ABZ) or mebendazole (MEB) ) are administered. However, there is a wide range of other brands, which are even more accessible, but for which the efficacy and quality remain poorly explored. We evaluated efficacy against STHs and quality of two ABZ brands commonly available on the local markets in Ethiopia (Bendex and Ovis). Both brands showed high efficacy against roundworm infections and poor efficacy against whipworms. However, for hookworm infections, Bendex was significantly less efficacious than Ovis. In terms of drug quality, a significant difference was observed in the dissolution profile, with Bendex having a significantly slower dissolution rate than Ovis. Since dissolution behavior is critical for a drug to be appropriately absorbed into the helminth (through host-blood and/or parasite-cuticle) and produce therapeutic efficacy, the poor dissolution of Bendex compared to Ovis can explain the observed difference in efficacy against hookworms. Our results emphasize the importance of periodically assessing of drug quality to ensure appropriate therapeutic efficacy and to exclude poor drug quality as a potential factor of reduced drug efficacy other than drug resistance.
Assessment of Efficacy and Quality of Two Albendazole Brands Commonly Used against Soil-Transmitted Helminth Infections in School Children in Jimma Town, Ethiopia