FormalPara Key Points

Oxantel pamoate is a safe and efficacious drug against Trichuris trichiura infections.

Oxantel pamoate is metabolically stable, shows low permeability and low systemic bioavailability after oral use.

The use of this drug in preventive chemotherapy as a combination treatment (e.g. with pyrantel pamoate) could greatly improve the success of this control strategy and prevent or postpone the development of resistance to benzimidazoles.

1 Background

Soil-transmitted helminths (Ascaris lumbricoides, hookworm and Trichuris trichiura) are the most widespread parasites in the world. They are most common in the poorest regions of the globe where education and access to sanitation and clean water are limited [1]. Soil-transmitted helminthiasis can lead to severe health consequences, particularly in children. For example, heavy infections with T. trichiura are often associated with chronic iron-deficiency anemia, chronic mucoid diarrhea, rectal bleeding, rectal prolapse, and finger clubbing in adults and children. Even mild infections with T. trichiura may be accompanied by growth retardation in children, while heavy infections may be linked to severe malnutrition and growth stunting [2].

Currently, the main control strategy used against these intestinal parasites is preventive chemotherapy, i.e. the regular distribution of a single dose of anthelminthic drugs to at-risk groups without prior diagnosis [3]. From 2010 to 2015, this low-cost strategy averted an estimated 44% of the disability-adjusted life-years (DALYs) in children [4]. However, the currently used drugs (usually mebendazole and albendazole) are not equally efficacious against all soil-transmitted helminth species [5]. Although these drugs are highly efficacious against A. lumbricoides, resulting in a 10% decline in its prevalence over the last years, they are only moderately efficacious against hookworm and poorly efficacious against T. trichiura [2]. Despite not being used as regularly as the benzimidazoles alone, levamisole, pyrantel pamoate and albendazole-ivermectin are also recommended by the World Health Organization (WHO) against soil-transmitted helminths (Table 1) [6]. However, with the exception of albendazole-ivermectin, no monotherapy drugs show acceptable efficacy (i.e. an egg reduction rate (ERR) > 90% based on the target product profile for drugs to be used for soil-transmitted helminths) when used as a single dose against T. trichiura infections [5, 7].

Table 1 Recommended preventive chemotherapy drugs (single-dose) and their efficacy against soil-transmitted helminth infections

An alternative anthelminthic compound discovered in the 1970s and known to be highly efficacious against T. trichiura is oxantel pamoate. Oxantel pamoate is a tetrahydropyrimidine derivative (Fig. 1) that has been marketed for veterinary use in non-rodent species for several decades as an oral formulation at single doses of 55 mg/kg in dogs. Several drugs containing oxantel are currently commercialized by different pharmaceutical companies, for both veterinary and human use (Table 2).

Fig. 1
figure 1

Structure of oxantel pamoate [9]

Table 2 Veterinary and human medical products containing oxantel pamoate

One of the ultimate goals is to register oxantel pamoate for the treatment of T. trichiura infections (for all ages above one year) at a stringent regulatory authority and market it for countries endemic to this parasite. Currently, oxantel pamoate is only approved and marketed for human use in some countries of South America and Asia for children from six months of age onwards in combination with pyrantel pamoate (Quantrel®) (Table 2). The European Union funded project “Establishment of a pan-nematode drug development pipeline”, Helminth Drug Development Platform (HELP, aims to establish a pipeline of anthelminthic drug development candidates. In the framework of HELP, we conducted a thorough review of the available literature to determine if any existing data can be used to support clinical development for T. trichiura. Preclinical data from prior sponsors could unfortunately not be obtained. We also summarize results from key experiments on the binding affinity of oxantel pamoate to the human and rat nAChR, metabolism and intestinal epithelial permeability using Caco-2 cells, which were conducted during this process. Finally, in discussion with regulatory agencies, a clinical development plan has started to be defined.

2 Pharmacology

2.1 Pharmacodynamics (PD)

2.1.1 Primary Pharmacology

A study investigating the activity of oxantel pamoate against T. muris, the mouse-specific Trichuris nematode in vitro, reported a half maximal inhibitory concentration (IC50) of 2.35 µg/mL, corresponding to 3.9 µM on L4 larvae (the last stage before the adult stage of Trichuris spp.) following incubation for 72 h [10]. In an in vivo experiment, different doses of oxantel pamoate, ranging from 1 to 10 mg/kg, were administered to mice infected with T. muris. The oral administration of 10 mg/kg achieved the highest worm burden reduction (93%) and worm expulsion rate (88%) and an ED50 value of 4 mg/kg was calculated [10], which is significantly lower than the one of other standard anthelminthics [11].

Following oral administration, oxantel pamoate acts locally in the human gastrointestinal tract by binding to the parasite’s nicotinic acetylcholine receptor (nAChR; neuronal (N)-type). Nicotinic acetylcholine receptors are widely expressed in the worms’ nervous system [12]. These receptors are present both on the neuromuscular junctions on the muscle cells and in the neurons themselves [12]. Oxantel pamoate activates the receptor that leads to an excitatory blockage with subsequent spastic paralysis and expulsion of the worm from the host’s gastrointestinal tract. However, the human gastrointestinal tract also has nAChRs that are structurally similar to those of nematodes and undergo similar mechanisms of gating [13]. The main difference lies in the location of these receptors since, in humans, nAChR is primarily located on intestinal epithelial (Caco-2) and enteric glial cells [13]. Still, the human nAChR could be stimulated by oxantel pamoate as well, which might result in secondary pharmacologic effects.

2.1.2 Secondary Pharmacology

In order to reveal the binding affinity of oxantel pamoate to the human and rat α7 nAChR, an in vitro receptor binding assay was conducted. Experimental details are summarized in Supplementary file 1. Receptors were isolated from human recombinant SH-SY5Y cells and from Wistar rat brain and incubated for 2 or 2.5 hours with oxantel pamoate at concentrations between 0.165 nM and 1.65 mM, respectively. Oxantel pamoate was found to bind to the human and rat receptors with IC50 values of 3.48 µM and 33.0 µM, respectively, which is in the same order of the IC50 value of 3.9 µM against T. muris that was described above. The positive control bungarotoxin showed a higher affinity to both human and rat receptors with IC50 values of 1.21 nM and 1.69 nM, respectively. However, due to the intended high dose of oral oxantel pamoate treatment (20 mg/kg), high intestinal concentrations are likely. Thus, local intestinal side effects of treatment with oxantel pamoate, which were already observed in clinical studies, might be due to interactions of oxantel pamoate with the human receptor expressed in the gastrointestinal tract. However, these effects observed in clinical studies were of short duration and reversible. The benefit of the drug seems to predominate potential short-term reversible adverse events.

2.2 Pharmacokinetics

2.2.1 Absorption and Distribution

The intestinal epithelial permeability of oxantel pamoate was investigated in an in vitro assay using Caco-2 cells (Supplementary file 2). Oxantel pamoate at a concentration of 10 µM was incubated with Caco-2 cells for 60 min at 37 °C. Four reference compounds with known high (propranolol, labetalol), moderate (ranitidine) and low (colchicine) intestinal permeability were incubated under the same conditions. With a mean apical to basolateral and basolateral to apical permeability of 0.2 and 0.4 × 10−6 cm/s, respectively, the permeability of oxantel pamoate was in the same range as colchicine and is, therefore, considered of low permeability in vitro (Table 3).

Table 3 Permeability of oxantel pamoate in Caco-2 cells

The low gastrointestinal absorption of oxantel pamoate was confirmed in a non-GLP (Good Laboratory Practice) study in rats. A single dose of 100 mg/kg oxantel pamoate was applied (together with 100 mg/kg albendazole). Blood samples were taken 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, and 33 hours post-treatment. At all time points, plasma levels of oxantel pamoate were below a lower limit of quantification (LLOQ) of 0.4 µg/mL (= 0.66 µM). This accounts for a bioavailability of < 0.025%, based on the assumption that the entire dose applied (100 mg/kg) would be absorbed and not metabolized, based on an average blood volume of 16 mL and a body weight of 250 g per rat [14]. Also, according to the core data sheet for Quantrel®, oxantel pamoate is poorly absorbed in the gastrointestinal tract because of its low aqueous solubility. It is stated that only around 8 to 10% is absorbed following a single dose of 10 mg/person and 0.5–1.8% at dose levels of 50 mg/kg; however, the underlying data could not be obtained [15]. Further pharmacokinetic (PK) studies will be embedded in the planned Phase I study (Box 1).

figure a

Box 1 Suggested clinical development plan for oxantel pamoate

2.2.2 Metabolism and Excretion

The metabolic stability was evaluated by incubating oxantel pamoate and reference compounds (midazolam, propranolol and terfenadine) at a respective concentration of 0.1 µM with human and rat intestinal microsomes (0.1 mg/mL) for 0, 30, 60, 90 and 120 min (experimental details are summarized in Supplementary file 3). Following incubations of oxantel pamoate with either rat or human intestinal microsomes up to 120 min, oxantel pamoate was considered metabolically stable with a calculated mean half-life of over 120 min in both rat and human intestinal microsomes (Table 4).

Table 4 Intrinsic stability of oxantel pamoate in rat and human intestinal microsomes

Since oxantel pamoate was found to be metabolically stable, only a very low intestinal permeability was observed in vitro and low oral bioavailability is expected; therefore, the investigation of hepatic metabolism was not considered applicable. It is assumed, that oxantel pamoate acts locally in the gastrointestinal tract following oral administration and is excreted unchanged via feces.

2.2.3 Pharmacokinetic Drug Interactions

The inhibition of cytochrome (CYP) enzymes by oxantel pamoate has been investigated in two published in vitro studies [14, 16]. Oxantel pamoate did not inhibit CYP1A2, CYP2C19 and CYP3A4 (IC50 > 100 µM) [14]. CYP2C9 and CYP2D6 were moderately inhibited by oxantel pamoate (IC50 = 7.8 µM and CYP2D6) [14]. In the second study, oxantel pamoate showed an inhibitory activity against CYP2C9 and CYP2D6 [16]. The inhibition of CYP1A2, CYP2C19, and CYP3A4 by oxantel pamoate was more pronounced than in a previous study by Cowan et al [14], which reported no interaction of oxantel pamoate with these enzymes. Overall, the risk for systemic drug-drug interaction is considered low due to the intended treatment schedule and low exposure.

2.3 Toxicity

Concerning single-dose toxicity, Marchiondo reported that oxantel pamoate was well tolerated in acute toxicity studies with median lethal dose (LD50) values of 300, 980 and 3200 mg/kg in mice, rats and rabbits, respectively [17]. Repeated-dose toxicity testing in rats will need to be conducted to explore any potential risk related to repeated administrations in humans and to examine the reversibility of findings, if any (Box 1). Local effects on the gastrointestinal tract will be explored in this 14-day repeated dose toxicity study in rats (Box 1). Since there are no published studies allowing for the definition of the genotoxicity risk, in vitro and in vivo testing will need to be conducted according to current regulatory requirements.

If a lack of biologically relevant systemic exposure is confirmed in the planned repeated-dose toxicity study in rats and the Phase I study, studies concerning reproductive and developmental toxicity, as well as phototoxicity, are not planned and are not considered to add value to the program. This also considers animal ethics. Carcinogenicity studies are not required considering the short oxantel pamoate treatment duration of a maximum of three days.

3 Clinical Efficacy

A PubMed search identified 15 studies, 11 of which were clinical trials assessing the efficacy of at least one treatment arm including oxantel pamoate alone or in combination with other drugs against T. trichiura. From the references of these 11 studies, another 14 were identified and will be mentioned in this review. The characteristics of each of these 25 studies are presented in Table 5. Only studies with a follow-up period between two and six weeks after treatment are listed.

Table 5 Characteristics of the clinical trials including oxantel pamoate in at least one treatment arm

The studies assessing the efficacy and safety of oxantel pamoate were conducted in two phases; the first phase took place in the 1970s followed by the second, which took place after the year 2000 with studies conducted by Swiss Tropical and Public Health Institute researchers. The earliest studies were performed in Asian countries and most had relatively small sample sizes, with the exception of the study by Lim and colleagues, which had a larger sample size [18]. Most studies were conducted with children and the most common diagnostic method was the Kato–Katz technique. It is likely that differences in infection intensity, as well as the different diagnostic methods used in the different studies (e.g. Kato Katz, formol-ether, Stoll) have an impact on the observed cure rates (CRs) and egg reduction rates (ERRs) [19, 20].

3.1 Trichuris trichiura Infections

Despite having relatively low sample sizes, the first trials using oxantel pamoate (sometimes in combination with pyrantel pamoate) already suggested a high efficacy of oxantel pamoate against T. trichiura (Table 6). All 17 studies conducted in the 1970s and early 1980s reported on the efficacy using CRs and, in most cases, ERRs; CRs ranged from 29% (with a single dose of oxantel, 10–20 mg/kg) to 100% (with 20 mg/kg of oxantel-pyrantel once per day for 2 days).

Table 6 Trichuris trichiura cure rates (%, CRs) and egg reduction rates (%, ERRs) resulting from all the treatment arms of clinical trials testing the efficacy of oxantel pamoate either alone or in combination with other drugs. The treatment arms were ranked from the highest to lowest CR

Several years later, a series of clinical trials testing oxantel pamoate alone and in combination with other drugs were conducted in Lao People’s Democratic Republic (PDR), Côte d’Ivoire and Pemba Island, Tanzania [38,39,40,41,42,43,44] (Table 6). In these trials, the treatment arms with the highest efficacy against T. trichiura all included oxantel pamoate with ERRs reaching up to 100%, showing that this drug is clearly superior to most available drugs. However, CRs varied considerably among studies.

In a dose-ranging study, Moser and colleagues identified 5 mg/kg as the minimum effective dose and 22 mg/kg was modelled as the maximum effective dose [41]. A weight-independent dose of 500 mg oxantel pamoate for sub-Saharan African children was proposed by the authors. With this dose, 95% of sub-Saharan African school-aged children would receive a minimum of 11.7 mg/kg and a maximum of 32.0 mg/kg oxantel pamoate [41].

A recent network meta-analysis based on data from six randomized controlled studies confirmed the high efficacy of oxantel pamoate against T. trichiura [8]. The authors found that a 20 mg/kg single dose of oxantel pamoate resulted in a significantly higher CR (76%) and ERR (85%) than the monotherapies of albendazole, pyrantel pamoate and tribendimidine.

3.2 Ascaris lumbricoides and Hookworm Infections

Despite its high efficacy against T. trichiura, laboratory studies [10] and clinical trials found a wide range of efficacy of oxantel pamoate for the other two soil-transmitted helminths. For A. lumbricoides, CRs ranged from 2 to 100% and for hookworm from 10 to 100%. Of note, the highest efficacies were reported by the oldest studies. On the other hand, the dose-ranging study conducted by Moser and colleagues revealed a low efficacy of oxantel pamoate against A. lumbricoides and hookworm [41]. However, when combined with albendazole, mebendazole, pyrantel pamoate, or tribendimidine, the efficacy of oxantel pamoate against these two parasites increased considerably, reaching up to 100% CR and 100% ERR [42, 44].

4 Clinical Safety

Side effects of the administration of oxantel pamoate are believed to be due to interactions between oxantel pamoate and the human nAChRs located in intestinal cells. Only a few of the studies from the 1970/80s reported side effects from a single dose of oxantel pamoate (Table 7). Clinical trials implemented after the year 2000 reported adverse events in more detail, presenting the number and proportion of adverse events by treatment arm. These studies found that oxantel pamoate was well tolerated by participants, with adverse events being mild to moderate. The frequency of adverse events seemed to be independent of the oxantel pamoate dose [41]. In many cases, participants already suffered from the same adverse events prior to treatment. No serious adverse event or death was ever reported. In all clinical trials, the most common adverse events were stomach pain and headache.

Table 7 Percentage of participants with adverse events in each treatment arm before treatment and 3 h, 24 h and 48 h after treatment

Only four studies administered more than one dose of oxantel pamoate, either 10 mg/kg once per day for three days alone or in combination with pyrantel pamoate [33, 45] or 15–20 mg/kg once per day for three days in combination with pyrantel pamoate [26]. Of these, only Garcia and colleagues reported to have one participant (3%) with an adverse event; no other studies reported adverse events in treatment arms with oxantel pamoate.

Also, according to Quantrel® (oxantel pamoate-pyrantel pamoate) package information leaflet, it is extremely well tolerated and side effects, if encountered, usually relate to the gastrointestinal tract. All adverse drug reactions identified during the post-marketing experience of Quantrel®, such as decreased appetite, insomnia, dizziness, somnolence, headache, abdominal pain, diarrhea, nausea, vomiting, cold sweat, hyperhidrosis, rash, pruritus and urticarial, were very rare (less than one case per 10,000).

Quantrel® is marketed for children who have 6 months of age or more. Although the absorption is known to be influenced by physiologic properties such as gastrointestinal fluid composition and volume, transit time, morphology, microbiota, and drug metabolizing enzymes, none of these properties differed much between one-year-old children and adults [46]. Therefore, no considerable difference regarding gastrointestinal absorption of oxantel pamoate is expected. Additionally, because no biologically relevant systemic exposure is assumed following oral application, although a role in organ development of nAChRs cannot be excluded based on the ubiquitous expression profile of nAChRs, substantial effects from acute oral dosing (1–3 days) of the drug on developing organs are considered unlikely in children aged one year and older.

Animal reproductive studies have found no teratogenic effects of oxantel pamoate. However, no well-controlled trials assessed the effect of oxantel pamoate in pregnant or lactating women [47, 48]. Therefore, breastfeeding should be discontinued if oxantel pamoate is administrated to the mother and the risk benefit needs to be carefully assessed before administering the drug to a pregnant woman [49].

5 Conclusions

Our review highlights that oxantel pamoate is, unlike the currently approved drugs, an excellent drug for treating T. trichiura infections. Oxantel pamoate has also been shown to be a safe drug that is already being used in children aged > 6 months. Thus, we believe that this drug would be a very important addition to the depleted drug armamentarium, not only because of its high efficacy, but also because it can contribute to delaying or even preventing development of resistance to the currently available treatment options. While reviewing the literature and preparing the briefing book prior to discussions with regulatory authorities we identified additional studies, which are summarized in this review (Box 1). Efforts will continue in the framework of HELP to fill the remaining knowledge gaps so that oxantel pamoate can be available for treatment of T. trichiura infections in the near future.