Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

Malaria Journal

Research

Anne Miller¹  Wilbur Milhous²  Dennis Kyle²  Jetsumon Sattabongkot³  Srawuth Komcharoen⁴  Pranee Hansukjariya⁴  Rawiwan Imerbsin⁴  Montip Gettayacamin⁴  Colin Ohrt⁵  Geoffrey S Dow⁵  David Kenworthy⁶  Simon Cozens⁶  Jim Veazey⁷ 

[1] CPMS, QSi, GlaxoSmithKline, Mail Cose UW2431, 709 Swedeland Road, 19406, King of Prussia, PA, USA;College of Public Health, University of South Florida, 3720 Spectrum Blvd, 33612, FL, USA;Department of Entomology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, 315/6, Rajthevi, 10400, Bangkok, Thailand;Department of Veterinary Medicine, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, 315/6, Rajthevi, 10400, Bangkok, Thailand;Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, 20910, Silver Spring, MD, USA;GlaxoSmithKline R&D, Drug Metabolism and Pharmacokinetics, Park Road, SG12 0DP, Ware, Hertfordshire, UK;US Army Medical Material Development Activity MCMR-UMP, 1430 Veterans Drive Fort Detrick, 21702-9232, MD, USA;

关键词: Chloroquine;    Mefloquine;    Vivax Malaria;    Artemether;    Radical Cure;   

DOI  :  10.1186/1475-2875-10-212

 received in 2010-12-28, accepted in 2011-07-29,  发布年份 2011

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Dow et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.