Summary: | <p>Abstract</p> <p>Background</p> <p>Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of <it>Plasmodium vivax</it>. 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.</p> <p>Methods</p> <p>In 2005, the radical curative efficacy of tafenoquine combinations was investigated in <it>Plasmodium cynomolgi</it>-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.</p> <p>Results</p> <p>The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg <it>versus </it>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 <it>versus </it>550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies.</p> <p>Conclusions</p> <p>Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against <it>P. vivax </it>hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.</p>
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