Safety, Pharmacokinetics, and Mosquito‐Lethal Effects of Ivermectin in Combination With Dihydroartemisinin‐Piperaquine and Primaquine in Healthy Adult Thai Subjects

Abstract

Mass administration of antimalarial drugs and ivermectin are being considered as potential accelerators of malaria elimination. The safety, tolerability, pharmacokinetics, and mosquito-lethal effects of combinations of ivermectin, dihydroartemisinin-piperaquine, and primaquine were evaluated. Coadministration of ivermectin and dihydroartemisinin-piperaquine resulted in increased ivermectin concentrations with corresponding increases in mosquito-lethal effect across all subjects. Exposure to piperaquine was also increased when coadministered with ivermectin, but electrocardiograph QT-interval prolongation was not increased. One subject had transiently impaired liver function. Ivermectin mosquito-lethal effect was greater than predicted previously against the major Southeast Asian malaria vectors. Both Anopheles dirus and Anopheles minimus mosquito mortality was increased substantially (20-fold and 35-fold increase, respectively) when feeding on volunteer blood after ivermectin administration compared with in vitro ivermectin-spiked blood. This suggests the presence of ivermectin metabolites that impart mosquito-lethal effects. Further studies of this combined approach to accelerate malaria elimination are warranted.

Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects

“…The insecticidal activity of ivermectin and its specific effect on Anopheles mosquito prompted an investigation into its antiplasmodial activity against the malaria parasite in order to use it for malaria treatment [102]. The antiplasmodial and insecticidal effects of ivermectin often depend on the concentration, route of administration, duration, species type, and experimental design [103]. Ivermectin was reported to inhibit the development of P. falciparum at the asexual stage with IC 50 in the range of 1-10 µg/mL, however, ivermectin had no effect at concentrations of 3.9-1000 ng/mL on P. vivax [104].…”

“…A different observation on the process by which ivermectin inhibits the growth of mosquitoes when infected with P. falciparum [106]. Kobylinski et al [103] reported that ivermectin decreased the intensity and prevalence of oocyst in different mosquitoes, while de Carvalho et al and Perez-Garcia et al [104,107] reported a reduction in the prevalence of oocyst without affecting the intensity in mosquito infected with P. falciparum and P. vivax. Three different avermectins were also tested with respect to the hepatic effect of Plasmodium.…”

Identification of the metabolites of ivermectin in humans

“…Venous blood was collected from three healthy Thai volunteers given a single dose of IVM (400 μg/kg) (NCT02568098) (Kobylinski et al, 2020). The blood samples were collected in sodium heparin tubes at 24 hours post IVM ingestion and kept frozen at -80°C until LC-MS/MS analysis.…”

“…Malaria is a mosquito-borne disease transmitted by Anophelesmosquitoes during blood feeding. Numerous studies have reported the mosquito-lethal effect of ivermectin (Chaccour et al, 2013;Kobylinski et al, 2020;Smit et al, 2018) and the ability to inhibit sporogony ofPlasmodium in the mosquito (Kobylinski et al, 2012;Kobylinski et al, 2017;Pinilla et al, 2018). Mass drug administration (MDA) of IVM has been suggested as a possible vector control tool to aid malaria elimination as it has been shown to reduce Plasmodiumtransmission by mosquitoes (Alout et al, 2014) and reduce transmission to humans (Foy et al, 2019).…”

“…Mass drug administration (MDA) of IVM has been suggested as a possible vector control tool to aid malaria elimination as it has been shown to reduce Plasmodiumtransmission by mosquitoes (Alout et al, 2014) and reduce transmission to humans (Foy et al, 2019). A recent clinical trial in Thailand showed that mosquito lethal effects persisted well beyond the detectable presence of the parent compound which suggests that IVM may have active metabolites that are more slowly eliminated than the parent compound (Kobylinski et al, 2020).…”