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

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. 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.

• Authors: Pattaraporn Vanachayangkul, Rawiwan Im-Erbsin, Anchalee Tungtaeng, Chanikarn Kodchakorn, Alison Roth, John Adams, Chaiyaporn Chaisatit, Piyaporn Saingam, Richard J Sciotti, Gregory A Reichard, Christina K Nolan, Brandon S Pybus, Chad C Black, Luis A Lugo-Roman, Matthew D Wegner, Philip L Smith, Mariusz Wojnarski, Brian A Vesely, Kevin C Kobylinski
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 64 Issue 9 (08 20 2020) ISSN: 1098-6596 [Electronic] United States
• PMID: 32660993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Vanachayangkul et al.

Chemical References

• Antimalarials
• Drug Combinations
• Ivermectin
• Chloroquine

Topics

• Animals
• Antimalarials (blood, pharmacokinetics, pharmacology)
• Biological Availability
• Chloroquine (blood, pharmacokinetics, pharmacology)
• Drug Administration Schedule
• Drug Combinations
• Drug Synergism
• Female
• Hepatocytes (drug effects, parasitology)
• Ivermectin (blood, pharmacokinetics, pharmacology)
• Liver (drug effects, parasitology)
• Macaca mulatta
• Malaria (drug therapy, parasitology)
• Male
• Parasitemia (drug therapy)
• Plasmodium cynomolgi (drug effects, growth & development, pathogenicity)
• Primary Cell Culture
• Schizonts (drug effects, growth & development)