ReviewIvermectin: From theory to clinical application
Introduction
Campbell and Omura were awarded the 2015 Nobel Prize in Physiology or Medicine for their discoveries regarding avermectin [1]. The avermectins were discovered in 1967 in fermentation broth of an actinomycete culture in Japan [2]. It was then found that avermectins are produced by Streptomyces avermitilis in the soil [3], [4]. The avermectins are a class of macrocyclic lactones (MLs) with nematocidal, acaricidal and insecticidal activities [2]. MLs, including the avermectins, have gained a valuable therapeutic role since the 1980s as antiparasitic drugs for animals and humans [5].
The first avermectin drug was introduced as a veterinary drug by Merck & Co. in 1981 [6], and new formulations of ivermectin (IVM), a derivative of avermectin, were released almost every year. There was very little motivation to produce IVM for the human health market until its efficacy against filarial nematodes was shown. IVM was first registered as a human drug under the brand name Mectizan® in 1987 and was first used to treat onchocerciasis in humans in 1988 [7]. IVM was the only member of the MLs approved for human use until the recent approval of moxidectin by the US Food and Drug Administration (FDA) in June 2018 for the treatment of onchocerciasis in humans [8]. They have been labelled as ‘wonder drugs’ [9].
IVM is a derivative of naturally-produced avermectin B1, comprised of approximately 80% 22,23-dihydro-avermectin B1a (molecular weight, 875.10 g/mol) and approximately 20% 22,23-dihydro-avermectin B1b (molecular weight, 861.07 g/mol) [10]. Oral IVM is the only licensed route of administration for human use, although it has been given successfully subcutaneously and topically [11], [12].
IVM is incompletely absorbed following oral administration, with a peak plasma concentration achieved in approximately 4 h. Oral IVM is available in different forms, i.e. solution, tablets or capsules, however the solution has approximately twice the systemic availability compared with the solid forms (tablets and capsules). Owing to the high lipid solubility of IVM, its administration following a high-fat meal increases its bioavailability by approximately 2.5-folds [5]. IVM is metabolised in human liver microsomes by a cytochrome P450 (CYP) enzyme, converting the drug to at least 10 metabolites, mostly hydroxylated and demethylated derivatives [13]. IVM and its metabolites are excreted mainly in the faeces in about 12 days. Only small amounts (<1%) are excreted in urine. The plasma half-life of IVM ranges from 9.8–14.3 h and about 3 days for the metabolites [5].
IVM is an endectocide, i.e. active both against endoparasites and ectoparasites. Beside filarial nematodes, IVM is effective against a number of soil-transmitted helminths, myiasis and scabies. Since its discovery, the antiparasitic uses of IVM have increased and continue to accumulate [1].
This review highlights the most common clinical uses of IVM, with special reference to the promising impact of IVM against other parasitic infections as well as the new formulations of IVM and their progress in the field.
Section snippets
Mechanism of action
MLs affect various life stages of many nematode and arthropod species, which can be attributed to modulation of the Cys-loop family of ligand-gated ion channels including glutamate-gated chloride channels (GluCls) [14]. IVM increases chloride conductance resulting in a long-lasting hyperpolarisation and less formation of action potentials and blocking of further functions [15]. It affects the motor neurons, interneurons and pharyngeal muscle cells leading to general locomotor paralysis, and
Current clinical uses of ivermectin
IVM use has increased worldwide to overcome many parasitic diseases infecting millions of people, such as strongyloidiasis (infecting about 100 million people) and onchocerciasis (infecting about 18 million people) [28].
Safety and side effects
No serious adverse events were reported in patients treated with IVM [97]. However, headache, dizziness, muscle pain, nausea or diarrhoea may occur. Moreover, low IVM levels are detected in human breast milk after a single oral dose of 150–250 µg/kg for up to 14 days. Likewise, studies in experimental animals showed teratogenicity at 400 µg/kg given to the mother [90]. On the other hand, it was estimated that in Onchocerca-endemic areas, up to 50% of pregnant women in the first trimester are
Potential drug resistance
Many studies have reported that intensive use of MLs creates a drug pressure on parasite populations and leads to the emergence of drug resistance in small ruminants, cattle and some humans. However, exploring the mechanisms responsible for this resistance remains an important challenge today [112], [113].
Resistance to IVM had been previously found in nematodes infecting animals. Human resistance of O. volvulus to IVM was reported as a suboptimal response to IVM treatment in Sudan [114],
Future perspectives and concluding remarks
Drug delivery systems can affect drug pharmacokinetics, the duration of its therapeutic effect and toxicity. Innovative drug delivery approaches and formulations such as slow-release formulations, IVM skin patches and IVM-impregnated clothing are being developed [11].
IVM nanoformulations can prolong the microfilaricidal action, which has a great potential in endemic areas compared with conventional treatments mostly due to improvement of poor pharmacokinetics or bioavailability of the drug [127]
Funding
None.
Competing interests
None declared.
Ethical approval
Not required.
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