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Abstract
BackgroundTafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns.MethodsIn 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans.ResultsThe total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies.ConclusionsTen-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.
Highlights
Tafenoquine is an 8-aminoquinoline being developed for radical cure of Plasmodium vivax
Patency and relapse patterns amongst P. cynomolgiinfected rhesus monkeys and utility of different chloroquine regimens (Cohorts 1-3) In the present series of three cohorts of monkeys, representing fifty four animals, patency was consistently observed in all cases on Day 8
At the time of the study, and in the absence of chloroquine and desethyl-chloroquine concentrations which were determined later, the research team was concerned that this might represent a failure of the three day regimen
Summary
Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. The compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. The 8-aminoquinoline class is the only class that kills key survival stages of the parasite - Plasmodium vivax hypnozoites and stage 5 Plasmodium falciparum gametocytes. It is currently in Phase II/III clinical trials for the radical cure of P. vivax malaria, in a one-day regimen as a consequence of its long half-life [1]. In two recent case reports, tafenoquine was administered alone to two patients with acute P. vivax malaria instead of the normal sequential combination of chloroquine (1500 mg over three days) and primaquine (420 mg over 14 days, [2]).
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