Revision Year: 2018 Publisher: SUBSTIPHARM DEVELOPPEMENT, 24 rue Erlanger, 75016 Parijs, Frankrijk
Pharmacotherapeutic group: Anthelmintics
ATC code: P02CF01
Ivermectin is derived from avermectins isolated from fermentation broths of Streptomyces avermitilis. It has high affinity with glutamate-gated chloride channels present in invertebrate nerve and muscle cells. Its binding to these channels promotes an increase in membrane permeability to chloride ions, leading to hyperpolarization of the neural or muscle cell. This results in neuromuscular paralysis and may lead to the death of certain parasites.
Ivermectin also interacts with other ligand-gated chloride channels such as the one involving the GABA neurotransmitter (gamma-aminobutyric acid). Mammals do not have glutamate-gated chloride channels. Avermectins have only low affinity for other ligand-gated chloride channels. They do not readily cross the blood/brain barrier.
Clinical studies conducted in Africa, Asia, South America, the Caribbean and Polynesia reveal a reduction (to less than 1%) in Wuchereria bancrofti microfilaraemia in the week following administration of an oral ivermectin dose of at least 100 μg/kg. These studies showed a dosedependent effect over the time during which the reduction in microfilaraemia and the infestation rate in the populations treated is maintained.
By treating microfilaraemia in man (the sole parasite reservoir for Wuchereria bancrofti), administration of mass treatment seems to be useful in terms of limiting the transmission of Wuchereria bancrofti by vector insects and interrupting the epidemiological chain.
Treatment with a single ivermectin dose of 200 micrograms per kg body weight has been shown to be effective and well-tolerated in patients with normal immunity and in whom infestation by Strongyloides stercoralis is restricted to the digestive tract.
The mean peak plasma concentration of the major component (H2B1a) observed about 4 hours after oral administration of a single 12 mg dose of ivermectin in tablet form is 46.6 (± 21.9) ng/mL.
The plasma concentration increases with increasing doses in a generally proportional manner. Ivermectin is absorbed and metabolised in the human body. Ivermectin and/or its metabolites are excreted almost exclusively in the faeces, whilst less than 1% of the administered dose is excreted in the urine. An in vitro study conducted on human liver microsomes suggests that cytochrome P450 3A4 is the main isoform involved in the hepatic metabolism of ivermectin. In humans, the plasma half-life of ivermectin is about 12 hours and that of the metabolites is about 3 days.
Preclinical studies suggest that ivermectin used at oral therapeutic doses does not significantly inhibit CYP3A4 (IC50 = 50 μM) or other CYP enzymes (2D6, 2C9, IA2 and 2E1).
Single-dose toxicity studies conducted in animals showed toxicity to the central nervous system, as manifested by the appearance of mydriasis, tremors and ataxia at high doses in several species (mice, rats and dogs), as well as vomiting and mydriasis in monkeys. Following administration of repeated doses of ivermectin close or equal to maternotoxic doses, foetal abnormalities (cleft palate) were observed in several animal species (mice, rats, rabbits). From these studies, it is difficult to assess the risk associated with administration of a single low dose. Standard studies conducted in vitro (Ames test, mouse lymphoma TK assay) did not show any genotoxicity. Nevertheless, no genotoxicity or carcinogenicity studies were conducted in vivo.
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