Ivermectin

Ivermectin is a member of the avermectin class. Avermectin has anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines. Anti-inflammatory properties of cutaneous ivermectin have been observed in animal models of skin inflammation. Ivermectin also causes death of parasites, primarily through binding selectively and with high affinity to glutamate-gated chloride channels, which occur in invertebrate nerve and muscle cells.

The mechanism of action of ivermectin in treating the inflammatory lesions of rosacea is not known but may be linked to anti-inflammatory effects of ivermectin as well as causing the death of Demodex mites that have been reported to be a factor in inflammation of the skin.

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.

Oral administration

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).

Topical application

Absorption

The absorption of ivermectin after cutaneous application was evaluated in a clinical trial in adult subjects with severe papulopustular rosacea under maximal use conditions. At steady state (after 2 weeks of treatment), the highest mean (± standard deviation) plasma concentrations of ivermectin peaked within 10 ± 8 hours post-dose (C_max: 2.1 ± 1.0 ng/mL range: 0.7-4.0 ng/mL) and the highest mean (± standard deviation) AUC_0-24hr was 36± 16 ng.hr/mL (range: 14-75 ng.hr/mL). Ivermectin systemic exposure levels reached a plateau by two weeks of treatment (steady state conditions). In the longer treatment durations of the Phase 3 studies, ivermectin systemic exposure levels were similar to those observed after two weeks of treatment. At steady state conditions, the ivermectin systemic exposure levels (AUC_0-24hr:36 ± 16 ng.hr/mL) were lower than those obtained following a single 6-mg oral dose of ivermectin in healthy volunteers (AUC_0-24hr:134 ± 66 ng.hr/mL).

Distribution

An in vitro study demonstrated that ivermectin is greater than 99% bound to plasma proteins and is bound primarily to human serum albumin. No significant binding of ivermectin to erythrocytes was observed.

Biotransformation

In vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4.

In vitro studies show that ivermectin does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 4A11 or 2E1. Ivermectin does not induce CYP450 enzyme expression (1A2, 2B6, 2C9 or 3A4) in cultured human hepatocytes.

Two major metabolites of ivermectin were identified in a maximal use clinical pharmacokinetic study and assessed during Phase 2 clinical studies (3"-O-demethyl ivermectin and 4a-hydroxy ivermectin). Similar to the parent compound, metabolites reached steady state conditions by 2 weeks of treatment, with no evidence of accumulation up to 12 weeks. Furthermore, the metabolites systemic exposures (estimated with C_max and AUC) obtained at steady state were much lower than those observed following oral administration of ivermectin.

Elimination

The terminal half-life averaged 6 days (mean: 145 hours, range 92-238 hours) in patients receiving a once daily cutaneous application of the medicinal product for 28 days, in the maximal use clinical pharmacokinetic study. Elimination is absorption-dependent following topical treatment with ivermectin. Pharmacokinetics of ivermectin have not been studied in patients with renal and hepatic impairment.

Oral administration

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.

Topical application

Repeat-dose studies up to 9 months via dermal application of ivermectin 10 mg/g cream in minipigs have not shown toxic effects or local toxicity at systemic exposure levels comparable to clinical exposure.

Ivermectin is not genotoxic in a battery of in vitro and in vivo tests. A 2-year carcinogenicity study via dermal application of ivermectin 10 mg/g cream in mice did not show any increased tumour incidence.

Reproductive toxicity studies after oral administration of ivermectin showed teratogenic effects in rats (cleft palates) and rabbits (carpal flexures) at high doses (exposure margin to the NOAEL at least 70-fold compared to the clinical exposure).

The neonatal toxicity in oral rat studies was not related to in utero exposure but to postnatal exposure through maternal milk which resulted in high levels of ivermectin in the brain and in plasma of offspring.

Ivermectin 10 mg/g cream has evidence of being skin irritant, sensitizing and photosensitising in Guinea pigs, but is not phototoxic.

Environmental Risk Assessment (ERA)

Ivermectin is very toxic for invertebrates and a risk has been identified for the aquatic, sediment and the terrestrial compartment. Care should be taken in order to prevent environmental contamination, in particular in the aquatic media.