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 <i>Plasmodium berghei</i> in orally dosed mice. Here, ivermectin showed inhibition of the <i>in vitro</i> development of <i>Plasmodium cynomolgi</i> 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 <i>P. cynomolgi</i> liver stages in rhesus macaques. No inhibition or delay to blood-stage <i>P. cynomolgi</i> 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) <i>in vitro</i> Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in <i>Plasmodium vivax</i> control and as adjunctive therapies against COVID-19 infections.