Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques

Abstract

<jats:p>Previously, ivermectin (1–10 mg/kg) was shown to inhibit liver-stage development of <jats:italic>Plasmodium berghei</jats:italic> in orally dosed mice. Here, ivermectin showed inhibition of the <jats:italic>in vitro</jats:italic> development of <jats:italic>Plasmodium cynomolgi</jats:italic> schizonts (IC<jats:sub>50</jats:sub> = 10.42 μM) and hypnozoites (IC<jats:sub>50</jats:sub> = 29.24 μM) in primary macaque hepatocytes when administered in high-dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for seven consecutive days was evaluated for prophylaxis or radical cure of <jats:italic>P. cynomolgi</jats:italic> liver-stages in Rhesus macaques. No inhibition or delay to blood-stage <jats:italic>P. cynomolgi</jats:italic> parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for seven days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) <jats:italic>in vitro</jats:italic>. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in <jats:italic>Plasmodium vivax</jats:italic> control and as adjunctive therapies against COVID-19 infections.</jats:p>

Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids

“…Further, IVM reduced in vitro development of P. cynomolgy schizonts (IC 50 = 10.42 μM) and hypnozoites (IC 50 = 29.24 μM) in rhesus macaque hepatocytes 43 . Finally, a recently-developed bioluminescence-based assay 44 enabled demonstrating that IVM and other avermectins inhibit the sporogonic development of P. berghei in an in vitro setting 45 .…”

Pre-erythrocytic Activity of M5717 in Monotherapy and Combination in Preclinical Plasmodium Infection Models

“…Other drug combinations have since been evaluated in the pre-erythrocytic context, such as the combination of several antiretroviral drugs 21 or of metformin with primaquine 22 against rodent Plasmodium infection, and of ivermectin and chloroquine against P. cynomolgi in rhesus macaques. 23 Our study now adds to the scarce information available on the pre-erythrocytic activity of antiplasmodial drug combinations and further validates the physiologically relevant 3D in vitro hepatic platform to provide data that correlates with the outcome of drug evaluation in vivo .…”

Ivermectin: A Promising Therapeutic for Fighting Malaria. Current Status and Perspective

“…These findings indicated inhibition of the onset of blood-stage parasitemia by impairment of the growth of liver parasites by 2 . On the other hand, in a stage-specific study, moderate in vitro inhibition of liver-stage schizonts (IC 50 = 10.42 μM) and hypnozoites was noted in Plasmodium cynmologi-infected rhesus macaque hepatocytes when 2 was administered prophylactically. Also, when administered alone (0.3, 0.6, 0.12 mg/kg) or in combination with 19 (10 mg/kg), 2 did not inhibit or delay blood-stage parasitemia.…”

“…It reduces nematode transmission by killing ,, the transmissible microfilaria stages and impairs the development and fecundity of adult worms in humans. This has been attributed to the impact of 2 on the neuromuscular physiology of invertebrates. , Several studies dealing with the detrimental effects of 2 on different stages − of the life-cycle of malaria parasites (the hepatic and erythrocytic stages), including vector control (vide infra), have been reported.…”