1. Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques
- Author
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Mariusz Wojnarski, Chanikarn Kodchakorn, Alison Roth, Luis A Lugo-Roman, Chaiyaporn Chaisatit, Pattaraporn Vanachayangkul, Philip L. Smith, Christina K. Nolan, John H. Adams, Chad C. Black, Kevin C. Kobylinski, Anchalee Tungtaeng, Rawiwan Imerbsin, Richard J. Sciotti, Brian Vesely, Piyaporn Saingam, Gregory A. Reichard, Brandon S. Pybus, and Matthew D Wegner
- Subjects
Male ,safety ,Plasmodium ,030231 tropical medicine ,Plasmodium vivax ,Primary Cell Culture ,Schizonts ,Biological Availability ,Parasitemia ,Pharmacology ,Drug Administration Schedule ,chloroquine ,ivermectin ,03 medical and health sciences ,Antimalarials ,0302 clinical medicine ,Ivermectin ,Pharmacokinetics ,Chloroquine ,parasitic diseases ,medicine ,Animals ,Pharmacology (medical) ,Plasmodium berghei ,Adverse effect ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,SARS-CoV-2 ,macaque ,COVID-19 ,Drug Synergism ,biology.organism_classification ,medicine.disease ,Macaca mulatta ,Bioavailability ,Malaria ,Drug Combinations ,Infectious Diseases ,Liver ,Hepatocytes ,Female ,business ,pharmacokinetics ,medicine.drug ,Plasmodium cynomolgi - Abstract
Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 μM) and hypnozoites (IC50, 29.24 μM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode., Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 μM) and hypnozoites (IC50, 29.24 μM) in primary macaque hepatocytes when administered as a 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 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi 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 7 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) in vitro. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.
- Published
- 2020