Open AccessSafety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques
Author(s) -
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 Pybus,
Chad Black,
Luis A. LugoRoman,
Matthew D. Wegner,
Philip L. Smith,
Mariusz Wojnarski,
Brian A. Vesely,
Kevin C. Kobylinski
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00741-20
Subject(s) - plasmodium berghei , chloroquine , ivermectin , pharmacokinetics , biology , pharmacology , plasmodium (life cycle) , malaria , virology , rhesus macaque , macaque , in vitro , immunology , parasite hosting , zoology , paleontology , biochemistry , world wide web , computer science
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 [IC 50 ], 10.42 μM) and hypnozoites (IC 50 , 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.