Ivermectin

DRUG CLASS

• macrocyclic lactone derived from Streptomyces avermitilis

PHARMACEUTICS

• Mixture of 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b (80:20 ratio)
• oral solution, tablets or capsules
• Topical 0.2% or 0.5% lotions
• Veterinary formulations may be higher concentration and/or contain excipients that have uncertain safety in humans

DOSE

• Single dose of 150-200 mcg/kg PO for most indications

INDICATIONS

• Onchocerciasis (annual dose required)
• Strongyloidiasis (second dose at 1 week)
• Lymphatic filiariasis (annual dose combined with albendazole 400mg)
• Other intestinal nematode infections (e.g. ascariasis, enterobiasis; less effective for trichuriasis or hookworm)
• Cutaneous larva migrans
• Scabies (uncomplicated; repeat dose at 1-2 weeks)
• Head lice (lotion)

CONTRA-INDICATIONS

• Avoid in conditions that disrupt the blood-brain barrier (e.g. trypanosomiasis, meningitis) due to risk of GABA receptor-mediated toxicity
• Loasis (risk of Loa encephalopathy)
• Children <5 years-old or <15kg weight
• Ivermectin is not indicated for the treatment or prevention of COVID19

MECHANISM OF ACTION

Anthelmintic effect

• binding and activating glutamate-gated chloride channels (GluCls) expressed on nematode neurons and pharyngeal muscle cells.
  • causes increased permeability of chloride ions and hyperpolarization
  • resulting in paralysis and death of the parasite
• Similar effect in other invertebrates such as insects
• Other effects have also been proposed (e.g. modulation of nematode immune response; interaction with other chloride channels)
• Glutamate-gated chloride channels (GluCls) are not found in mammals, but ivermectin does bind mammalian GABA receptors (albeit with 100-fold lower affinity) and acts as a GABAergic agonist in higher concentrations.

Antiviral effect

• binds the importin (IMP) alpha/beta1 heterodimer, which is responsible for the nuclear import of viral proteins such as the integrase (IN) protein
• inhibits nuclear import of host and viral proteins required for viral replication
• This effect has only been found in in vitro studies for the SARS-CoV2 virus using high doses of the drug that are not safe for use in humans (e.g. 50 times the typical anti-helminthic therapeutic concentration in humans (Chaccour et al, (2020)) 

Anti-malarial and anti-cancer effects of ivermectin have also been proposed.

PHARMACOKINETICS

• A: peak levels at 4-5h after oral administration
• D: 10L/kg VD; 93% protein bound; does not cross readily cross intact blood-brain barrier due to P-glycoprotein efflux
• M: extensive hepatic metabolism by CYP3A4 (mostly hydroxylation and demethylation)
• E: t1/2 ~57 hours; 1-2 L/min systemic clearance; multiple inactive metabolites excreted in urine 

DRUG-DRUG INTERACTIONS (DDI)

• Risk of interactions with other drugs that are CYP3A4 inhibitors or affect P-glycoprotein transport
• May increase effect of warfarin
• Avoid concurrent use of GABaergic medications (e.g. benzodiazepines, barbiturates, ethanol)

PREGNANCY/LACTATION

• Sometimes avoided as enters breast milk in low concentrations and concerns ivermectin may cross immature blood-brain barrier, but need to consider risk-benefit (e.g. underfeeding of breast fed infants in low income countries)
• Uncertain safety in pregnancy (avoid)

ADVERSE EFFECTS 

• Mazzotti-like reaction to dying microfilariae:
  • mild – pruritis, lymphadenopathy (treat with antihistamines) 
  • severe – fever, diarrhoea, tachycardia, hypotension, dizziness, headache, myalgia, arthralgia, facial and peripheral oedema (treat with corticosteroids)
• Loa encephalopathy in patients with Loasis
• Neurotoxicity from high doses (including ataxia, coma, and death)
• Hypersensitivity

EVIDENCE

Cochrane review of ivermectin for the prevention or treatment of COVID19 (Popp et al, 2021):

• 14 randomized controlled trials with 1678 participants; only one study assessing prevention
• Generally low quality evidence
• No evidence of benefit for ivermectin use

Ivermectin should not be used for prevention or treatment of COVID19 outside the context of clinical trials. 

OTHER

• Ivermectin has replaced hydroxychloroquine as the crackpot’s COVID19 “drug du jour” – with two high profile critical care doctors at the forefront – and some published research studies supporting ivermectin use have been identified as fraudulent.
  • A 2021 meta-analysis has been withdrawn and is being re-analysed as the only two trials in the study supporting the use of ivermectin for COVID19 have been shown to be fraudulent (Lawrence et al, 2021).
  • Nick Mark has written a comprehensive summary of the lack of evidence supporting ivermectin use for COVID19 outside of the context of clinical trials on the ICU One Pager blog.
• Use of ivermectin has skyrocketed during the COVID19 pandemic (as have cases of toxicity) despite statements by many regulatory and medical bodies (e.g. FDA, US CDC, and WHO) that it is not approved for the treatment or prevention of COVID-19 (see Wikipedia).
• The 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for the discovery of avermectin.

REFERENCES

FOAM and web resources

• Ivermectin | C48H74O14 – PubChem
• Business Insider – 2 fringe doctors created the myth that ivermectin is a ‘miracle cure’ for COVID-19 – whipping up false hope that could have deadly consequences (2021)
• Gideon M-K; Health Nerd – Is Ivermectin for Covid-19 Based on Fraudulent Research? (2021)
• ICU One Pager – Debunking Ivermectin: A Complete Guide (2021)

Journal articles and textbooks

• Chaccour C, Hammann F, Ramón-García S, Rabinovich NR. Ivermectin and COVID-19: Keeping Rigor in Times of Urgency. Am J Trop Med Hyg. 2020 Jun;102(6):1156-1157. doi: 10.4269/ajtmh.20-0271. PMID: 32314704; PMCID: PMC7253113. [article] 
• Brunton, LL, Hilal-Dandan R; Knollmann BC. 2017. Goodman & Gilman’s the Pharmacological Basis of Therapeutics  (13th ed.). New York: McGraw-Hill. ISBN 978-1259584732. p1006.
• Lawrence, J.M., Meyerowitz-Katz, G., Heathers, J.A.J. et al. The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable. Nat Med (2021). https://doi.org/10.1038/s41591-021-01535-y [article]
• Martin RJ, Robertson AP, Choudhary S. Ivermectin: an anthelmintic, an insecticide, and much more. Trends Parasitol 2021; 37:48–64. [article]
• Popp M, Stegemann M, Metzendorf MI, Gould S, Kranke P, Meybohm P, Skoetz N, Weibel S. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. 2021 Jul 28;7(7):CD015017. doi: 10.1002/14651858.CD015017.pub2. PMID: 34318930; PMCID: PMC8406455. [article]