Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine and chloroquine in Rhesus Macaques

Abstract

Ivermectin could be used for malaria control as treated persons are lethal to blood feeding Anopheles, resulting in reduced transmission. Tafenoquine could be used in combination with ivermectin to clear persons of liver stage Plasmodium vivax reservoir and as a prophylactic in high-risk populations. The safety of ivermectin and tafenoquine has not been evaluated. As earlier forms of 8-aminoquinolones were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein blood brain barrier transporter, there is concern that co-administration could be neurotoxic. The safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine was evaluated in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine with ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3"-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques, therefore this combination could be considered for evaluation in human trials.