title: Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).
abstract: BACKGROUND
  Tafenoquine 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Ten-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.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Dow
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: Pranee
authors.initials: P
authors.lastname: Hansukjariya
authors.forename: Rawiwan
authors.initials: R
authors.lastname: Imerbsin
authors.forename: Srawuth
authors.initials: S
authors.lastname: Komcharoen
authors.forename: Jetsumon
authors.initials: J
authors.lastname: Sattabongkot
authors.forename: Dennis
authors.initials: D
authors.lastname: Kyle
authors.forename: Wilbur
authors.initials: W
authors.lastname: Milhous
authors.forename: Simon
authors.initials: S
authors.lastname: Cozens
authors.forename: David
authors.initials: D
authors.lastname: Kenworthy
authors.forename: Anne
authors.initials: A
authors.lastname: Miller
authors.forename: Jim
authors.initials: J
authors.lastname: Veazey
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics; D002738:Chloroquine / Q000008:administration & dosage / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004338:Drug Combinations; D004359:Drug Therapy, Combination / Q000379:methods; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008253:Macaca mulatta / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D013058:Mass Spectrometry; D015767:Mefloquine / Q000008:administration & dosage / Q000493:pharmacokinetics; D010949:Plasma / Q000737:chemistry; D016789:Plasmodium cynomolgi; D018419:Primate Diseases / Q000188:drug therapy*; D011803:Quinine / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; C055852:tafenoquine; D002738:Chloroquine; D011803:Quinine; D015767:Mefloquine