Background
Essential pharmacology
Mechanism of action
The glutamate-gated chlorine channel in Anopheles gambiae
Pharmacokinetics
Absorption
Distribution
Metabolism and elimination
Assessing the efficacy of ivermectin to kill mosquitoes
The concept of lethal concentration 50 (LC50)
Pharmacokinetic considerations regarding efficacy
The mortality of mosquitoes caused by ivermectin has a dose–response gradient and is limited by the theoretical LC100
Ivermectin’s impact on mosquito mortality is directly related to the time there is a lethal concentration in the blood
The lethal effect is heterogenic
The lethal effect could be a function of the area under the curve
Conceptually, the ideal ivermectin dose would maximize the time drug level is near the LC100 without wasting drug going beyond the level at which most mosquitoes are killed
Time above lethality target
Dose–response curves
Options to increase the efficacy of ivermectin
Higher doses (increasing the Cmax)
Multi-dose regimens
Slow-release formulations
Other options
Other effects of ivermectin
Effect on vector fertility
Effects on vector behaviour
Key knowledge gaps regarding efficacy
Methods
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Lack of standardized protocols for the assessment of ivermectin’s efficacy.
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Lack of correlation between the mortality observed in mosquitoes taking ivermectin through membrane vs those taking it via skin-feeding. Validating membrane feeds as a reliable, predictive assay compared to direct skin-feeding would facilitate evaluation of different approaches.
Lc50
Time above lethality
Other effects
PK considerations regarding safety
Therapeutic index
Reference | Population | Highest single dose | Maximum frequency | Maximum number of doses | Maximum total dose (period) | Adverse events |
---|---|---|---|---|---|---|
Awadzi et al. [100] | 75 males with moderate to heavy Onchocerca infection | 800 mcg/kg | Single | Single | 800 mcg/kg (once) | No difference with controls taking the 150 mcg/kg dose |
Awadzi et al. [101] | 100 adult males infected with Onchocerca
| 800 mcg/kg | Days 1 and 4 | 2 | 1.600 mcg/kg (4 days) | No difference with controls taking the 150 mcg/kg dose |
Guzzo et al. [62] | 68 male and female healthy, adult volunteers | 2.000 mcg/kg | Days 1, 4 and 7 | 3 | 3.273 mcg/kg (1 week) | No difference with controls |
Kamgno et al. [67] | 657 adult males infected with Onchocerca
| 800 mcg/kg | 3-monthly | 13 | 8.950 mcg/kg (3 years) | The high dose group reported a statistically higher rate of transitory mild and subjective visual side effects (No structural explanation). For all other AE comparable rates reported in all groups |
Smit et al. [43] | 141 adults with uncomplicated malaria | 600 mcg/kg | Days 1, 2 and 3 | 3 | 1.800 mcg/kg (3 days) | Pending publication of results |
The efficacy/safety ratio
Safety profile of ivermectin in community campaigns–implications for malaria
Safety of ivermectin in onchocerciasis MDA campaigns
Loa-associated encephalopathy
Safety of ivermectin at doses higher or more frequent than approved for NTDs
Safety of ivermectin during pregnancy and lactation
Reference | Country | Number of pregnant women | Number inadvertently treated | In the first trimester | Pregnancy outcome | Child mortality | Child development |
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Pacque et al. [81] | Liberia | 939 | 200 | 171 (85%) | No difference with controls | No difference with controls | No difference with controls (follow-up 2 years) |
Doumbo et al. [102] | Mali | 461 | 82 | Not stated | Data not readily assessable | ||
Chippaux et al. [103] | Cameroon | 511 | 110 | (93) 85% | No difference with controls | No difference with controls | No difference with controls (follow-up 1 year) |
Gyapong et al. [104] | Ghana | 343 | 50 | (50) 100% | No difference with controls | No difference with controls | No difference with controls (follow-up not stated) |
Ndyomugyenyi et al. [105] | Uganda | 834 | 397a
| All in 2nd trimester | No difference with controls | No difference with controls | Not included |
Safety of ivermectin in infants and children
Safety of ivermectin in high-risk groups
Environmental concerns about ivermectin
Key knowledge gaps regarding safety
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The safety profile of ivermectin when used at higher doses, or with longer exposure treatment schemes.
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The safety of the proposed dose/schemes in populations likely to affect coverage if excluded i.e. potentially pregnant women and children under 15 kg.
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New strategies to assess and prevent the Loa-related adverse effects.
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The safety of ivermectin in combination with anti-malarials and other drugs commonly used in endemic areas such as antiretrovirals, TB drugs and other antihelmintics.