I won't quote this at length since it's not covid-19 related. It might be valuable for thinking about how the US and every other country with a covid-19 problem might address the application of ivermectin if it turns out to be the magic bullet. The key concept is MDA: Mass Drug Administration. Ivermectin has been distributed via MDAs for decades (I think) to fight river blindness and filariasis. This article is about extending ivermectin to fight malaria as well. A difference is that those parasites require only one dose annually. For malaria the benefit of ivermectin is much shorter lived.
Argh: There was too much to quote. I selected the dosing part, which has new information about dosing limits according to the EU and Australia.
#Efficacy.
The efficacy of ivermectin against malaria arises mainly from the mosquito-killing capacity of the drug when ingested during a blood meal. Additional sublethal effects that could affect the mosquito and/or the parasite in the mosquito and, therefore, malaria transmission, have also been described.29,30 Mosquitoes fed with ivermectin-containing blood have shown negative alterations on their fertility and flying ability.29,30 Likewise, the development of blood and liver-stage parasites has been inhibited by ivermectin in vitro and mouse models.31,32 However, the magnitude and mechanism of this effect in humans has yet to be fully studied. Because sublethal outcomes will require further elucidation, this report focuses exclusively on mosquito mortality as the primary determinant of ivermectin efficacy.
The lethality of ivermectin is a function of three key parameters: 1) concentration: drug blood levels reached, 2) time: the duration of the drug circulating at effective concentrations in blood, and 3) coverage: the proportion of blood sources covered (Figure 1). In other words, the mosquito-killing effect is intrinsically related to the ivermectin concentration reached in the subject (human or animal), the time this concentration is sustained in the blood, and the number of subjects reached.
#Dosing and regimen considerations.
The dose and regimen for ivermectin delivery must be designed to optimize impact while ensuring maximum safety. These are key factors that impact on the concentration and duration of ivermectin in blood and, therefore, the efficacy of the intervention. Ideally, mosquito-lethal concentrations of ivermectin would be sustained in the blood for as long as possible, while avoiding human toxicity and minimizing the number of MDA campaigns required. Ivermectin’s toxicity in humans is the result of cross-binding to GABA-gated channels which are only present in the central nervous system (CNS) and, hence, protected by the blood brain barrier (BBB). So, ivermectin toxicity in mammals is related to its level in the CNS, which is not necessarily related to the blood levels but to the integrity/maturity of the BBB and the activity of BBB-related efflux pumps such as the P-glycoprotein.34
The ivermectin label has been modified extensively over 30 years of treatment and prevention of NTDs. The current Federal Drug Administration (FDA)–approved ivermectin dose for onchocerciasis MDA is a single dose of 150–200 μg/kg yearly, although the possibility of quarterly use in individual patients is also included on the label for areas with high onchocerciasis transmission.35 For moderate to severe crusted scabies, three doses of 200 μg/kg within 2 weeks are recommended in the Stromectrol® Australian label.26 Of relevance, the 400 μg/kg single dose yearly MDA is included on the Mectizan® and the Stromectrol labels, both approved by the European Medicines Agency (EMA).
Currently, two potential regimens are being considered for malaria clinical trials (see section Assessment of expected impact). One is the single 400 μg/kg dose that is in the EMA-approved ivermectin label, repeated three times during the malaria season. The second is a three-dose regimen of 300 μg/kg taken on 3 consecutive days (days 1–3), in combination with the artemisinin-based combination therapy (ACT), dihydroartemisinin–piperaquine, in three rounds administered during the malaria season.37 During the roadmap development, a modeling exercise was performed to evaluate the impact of both options in different transmission scenarios (Slater, unpublished). Figure 2 displays an example of a three-round deployment of ivermectin 1 month apart, each right at the start of the rainy season, at either the 1 × 400 or the 3 × 300 dose in a perennial transmission setting in northern Mozambique. The effect of the intervention is shown as the variation of clinical incidence of malaria over time for both all-age and under-five populations. The model shows that three doses of 300 μg/kg, used monthly for 3 months, could reduce clinical infection incidence by 50%, whereas a single dose of 400 μg/kg would reduce it by about 40%. Notably, although the difference between the two regimens is potentially measurable at the population level, other factors to be taken into account are the delivery logistics, cost-effectiveness, and community acceptability of each option. In the 3 × 300 regimen, the first dose is directly observed, whereas the remaining two doses are unobserved. Although this model was successfully used in SMC programs,38 it could lead to adherence concerns, particularly over time. There is a risk that the concurrent use of a single dose for NTDs and multiple-dose regimens for malaria may create confusion and affect acceptability by the community. Alternatively, the successful delivery of a single higher dose of 400 μg/kg may achieve greater effectiveness at the community level without a significant trade-off in efficacy. A thorough comparison of the two approaches is shown in Table 3.
[-] TrumpLyftAlles | 1 points | Jun 11 2020 18:16:27
I won't quote this at length since it's not covid-19 related. It might be valuable for thinking about how the US and every other country with a covid-19 problem might address the application of ivermectin if it turns out to be the magic bullet. The key concept is MDA: Mass Drug Administration. Ivermectin has been distributed via MDAs for decades (I think) to fight river blindness and filariasis. This article is about extending ivermectin to fight malaria as well. A difference is that those parasites require only one dose annually. For malaria the benefit of ivermectin is much shorter lived.
Argh: There was too much to quote. I selected the dosing part, which has new information about dosing limits according to the EU and Australia.
#Efficacy. The efficacy of ivermectin against malaria arises mainly from the mosquito-killing capacity of the drug when ingested during a blood meal. Additional sublethal effects that could affect the mosquito and/or the parasite in the mosquito and, therefore, malaria transmission, have also been described.29,30 Mosquitoes fed with ivermectin-containing blood have shown negative alterations on their fertility and flying ability.29,30 Likewise, the development of blood and liver-stage parasites has been inhibited by ivermectin in vitro and mouse models.31,32 However, the magnitude and mechanism of this effect in humans has yet to be fully studied. Because sublethal outcomes will require further elucidation, this report focuses exclusively on mosquito mortality as the primary determinant of ivermectin efficacy.
The lethality of ivermectin is a function of three key parameters: 1) concentration: drug blood levels reached, 2) time: the duration of the drug circulating at effective concentrations in blood, and 3) coverage: the proportion of blood sources covered (Figure 1). In other words, the mosquito-killing effect is intrinsically related to the ivermectin concentration reached in the subject (human or animal), the time this concentration is sustained in the blood, and the number of subjects reached.
#Dosing and regimen considerations. The dose and regimen for ivermectin delivery must be designed to optimize impact while ensuring maximum safety. These are key factors that impact on the concentration and duration of ivermectin in blood and, therefore, the efficacy of the intervention. Ideally, mosquito-lethal concentrations of ivermectin would be sustained in the blood for as long as possible, while avoiding human toxicity and minimizing the number of MDA campaigns required. Ivermectin’s toxicity in humans is the result of cross-binding to GABA-gated channels which are only present in the central nervous system (CNS) and, hence, protected by the blood brain barrier (BBB). So, ivermectin toxicity in mammals is related to its level in the CNS, which is not necessarily related to the blood levels but to the integrity/maturity of the BBB and the activity of BBB-related efflux pumps such as the P-glycoprotein.34
The ivermectin label has been modified extensively over 30 years of treatment and prevention of NTDs. The current Federal Drug Administration (FDA)–approved ivermectin dose for onchocerciasis MDA is a single dose of 150–200 μg/kg yearly, although the possibility of quarterly use in individual patients is also included on the label for areas with high onchocerciasis transmission.35 For moderate to severe crusted scabies, three doses of 200 μg/kg within 2 weeks are recommended in the Stromectrol® Australian label.26 Of relevance, the 400 μg/kg single dose yearly MDA is included on the Mectizan® and the Stromectrol labels, both approved by the European Medicines Agency (EMA).
Currently, two potential regimens are being considered for malaria clinical trials (see section Assessment of expected impact). One is the single 400 μg/kg dose that is in the EMA-approved ivermectin label, repeated three times during the malaria season. The second is a three-dose regimen of 300 μg/kg taken on 3 consecutive days (days 1–3), in combination with the artemisinin-based combination therapy (ACT), dihydroartemisinin–piperaquine, in three rounds administered during the malaria season.37 During the roadmap development, a modeling exercise was performed to evaluate the impact of both options in different transmission scenarios (Slater, unpublished). Figure 2 displays an example of a three-round deployment of ivermectin 1 month apart, each right at the start of the rainy season, at either the 1 × 400 or the 3 × 300 dose in a perennial transmission setting in northern Mozambique. The effect of the intervention is shown as the variation of clinical incidence of malaria over time for both all-age and under-five populations. The model shows that three doses of 300 μg/kg, used monthly for 3 months, could reduce clinical infection incidence by 50%, whereas a single dose of 400 μg/kg would reduce it by about 40%. Notably, although the difference between the two regimens is potentially measurable at the population level, other factors to be taken into account are the delivery logistics, cost-effectiveness, and community acceptability of each option. In the 3 × 300 regimen, the first dose is directly observed, whereas the remaining two doses are unobserved. Although this model was successfully used in SMC programs,38 it could lead to adherence concerns, particularly over time. There is a risk that the concurrent use of a single dose for NTDs and multiple-dose regimens for malaria may create confusion and affect acceptability by the community. Alternatively, the successful delivery of a single higher dose of 400 μg/kg may achieve greater effectiveness at the community level without a significant trade-off in efficacy. A thorough comparison of the two approaches is shown in Table 3.
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