Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety

Abstract

Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways.

Keywords: Anopheles; Endectocide; Ivermectin; Pharmacokinetics.

Fig. 1

The PK curve of ivermectin. Plasma concentration of ivermectin in 10 Sudanese patients infected with onchocerciasis after a single oral 150 mcg/kg dose (Data from Elkassabi [28])

Fig. 2

The effect of increasing concentrations of ivermectin on its efficacy. Columns A, B and C are expected to have increasing efficacy. The area above the LC₁₀₀ in column D will not contribute to further mosquito mortality. In the absence of a long elimination tail, the efficacy of the dose of column C and that of column D will be equal. Columns are used for illustration. LC₁₀₀: lethal concentration 100

Fig. 3

Heterogeneity of mosquito mortality according to the ivermectin plasma concentration at the time of biting. LC₅₀ and LC₂₅ according to Kobylinski et al. [46]. The LC₉₅ and LC₇₅ shown have not been determined and are shown for illustration purposes. LC lethal concentration

Fig. 4

AUC of different dosing schemes and their potential relationship with efficacy. a The area of both columns is the same (A = B), hence, in the presence of constant biting rate, the total number of mosquitoes killed by A and B might me similar, even if B does not reach the same Cmax. b If the theoretical LC₁₀₀ is surpassed (light blue area), the drug consumed to reach such plasma levels is partly wasted because it does not contribute to efficacy and may in turn increase the possibility of side effects. Columns are used only for illustration. LC ₁₀₀ lethal concentration 100

Fig. 5

The time above lethality and the “mosquitocidal window”. An illustration of how the lethality target selected and the susceptibility of the local vectors can affect the efficacy of ivermectin to reduce malaria transmission. The curves represent the PK of ivermectin after a single oral 150 mcg/kg dose according to Elkassaby [28]. In both panels, the lethality target is the LC₅₀. The vectors of a are less susceptible and higher concentrations are required to kill 50% of them, the time above lethality target is 7 h. The vectors of b are much more susceptible, this increases the time above lethality eightfold. LC lethal concentration

Fig. 6

Logarithmic ivermectin dose–response curve as mosquitocidal. In the case of ivermectin, the dose will be a function of the AUC and the response a function of the total mosquito mortality plus the sublethal effects. AUC area under the curve

Fig. 7

Increasing efficacy using higher doses. Using a higher dose-per-body weight in a single encounter increases the AUC by increasing the Cmax. AUC area under the curve

Fig. 8

Increasing efficacy by means of multiple dosing. Using a series of multiple doses can increase the AUC while avoiding reaching plasma concentrations where the efficacy/safety ratio is lower

Fig. 9

Increasing efficacy with a slow-release formulation. A long lasting formulation would increase AUC by prolonging time above lethality, without significant increase in the Cmax and theoretically improving the efficacy/safety ratio. AUC area under the curve

Fig. 10

Therapeutic index. AUC area under the curve, MDA mass drug administration (Adapted from Golan et al. [61])

Fig. 11

The efficacy/safety ratio. The relationship between the efficacy: adverse effect ratio and the cumulative dose