Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review

Abstract

Soil-transmitted helminths (Ascaris lumbricoides, hookworm and Trichuris trichiura) infect about one-fifth of the world's population. The currently available drugs are all highly efficacious against A. lumbricoides. However, they are only moderately efficacious against hookworm and poorly efficacious against T. trichiura. Oxantel, a tetrahydropyrimidine derivative discovered in the 1970s, has recently been brought back to our attention given its high efficacy against T. trichiura infections (estimated 76% cure rate and 85% egg reduction rate at a 20 mg/kg dose). This review summarizes the current knowledge on oxantel pamoate and its use against T. trichiura infections in humans. Oxantel pamoate acts locally in the human gastrointestinal tract and binds to the parasite's nicotinic acetylcholine receptor (nAChR), leading to a spastic paralysis of the worm and subsequent expulsion. The drug is metabolically stable, shows low permeability and low systemic bioavailability after oral use. Oxantel pamoate was found to be safe in humans, with only a few mild adverse events reported. Several clinical trials have investigated the efficacy of this drug against T. trichiura and suggest that oxantel pamoate is more efficacious against T. trichiura than the currently recommended drugs, which makes it a strong asset to the depleted drug armamentarium and could help delay or even prevent the development of resistance to existing drugs. We highlight existing data to support the use of oxantel pamoate against T. trichiura infections.

Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from Trichuris muris

“…This is in line with oxantel pamoate primarily stays in the gastrointestinal tract where it is believed to interact with nAChRs located in human intestinal cells. However, Palmeirim et al (2021) [42] reviewed clinical trials implemented after 2000, and reported that the most common side effects described were stomach pain and headache.…”

“…A recent in vitro receptor binding assay reports oxantel to bind to the human α7 with an estimated maximal inhibitory concentration (IC 50 ) of 3.48 μM. A similar binding assay was performed using the whole brain membranes (minus cerebellum) from Wistar rats, which contains nAChR, here an estimated IC 50 value of 33 μM was reported [ 42 ]. For comparison, the IC 50 value of oxantel pamoate for the larvae stage 4 (L4) of T. muris has previously been reported to be 3.9 μM [ 20 ], which by the authors is categorized as in the same order as the IC 50 values for the mammalian nAChRs.…”

“…For comparison, the IC 50 value of oxantel pamoate for the larvae stage 4 (L4) of T. muris has previously been reported to be 3.9 μM [ 20 ], which by the authors is categorized as in the same order as the IC 50 values for the mammalian nAChRs. It should be noted that the authors emphasize the IC 50 values of the nAChRs to be interpreted with caution as data are insufficient [ 42 ]. The α7 subunit from chicken has been expressed in X. laevis oocytes and assayed with oxantel [ 43 ].…”

“…The mean apical to basolateral and basolateral to apical permeability was 0.2 and 0.4 × 10 −6 cm/s, respectively. This was in the same range as colchicine and was therefore by the authors considered to be low permeability [ 42 ]. The poor gastrointestinal drug absorption has been evaluated in vivo by Cowan et al [ 45 ] who found the plasma level concentrations to be below the limit of quantification after oral administration of 100 mg/kg oxantel pamoate to mice, the poor systemic bioavailability has also been confirmed in rats [ 46 ].…”

“…However, oxantel pamoate has been found to be metabolic stable when incubating oxantel pamoate with human and rat intestinal microsome. Due to the metabolic stability and poor absorption, hepatic metabolism has not been further evaluated [ 42 ]. It is assumed that oxantel pamoate primarily stays in the intestinal tract; however, further pharmacokinetic studies are suggested for Phase I studies [ 42 ].…”