Randomized Dose‐Ranging Study of the Safety and Efficacy of WR 238605 (Tafenoquine) in the Prevention of Relapse of<i>Plasmodium vivax</i>Malaria in Thailand

Walsh, Douglas S.; Looareesuwan, Sornchai; Wilairatana, Polrat; Heppner, D. Gray; Tang, Douglas B.; Brewer, Thomas G.; Chokejindachai, Watcharee; Viriyavejakul, Parnpen; Kyle, Dennis E.; Milhous, Wilbur K.; Schuster, Brian G.; Horton, John; Braitman, David J.; Brueckner, Ralf P.

doi:10.1086/315034

Cited by 89 publications

(88 citation statements)

References 15 publications

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“…4,6 In several clinical studies, tafenoquine was also tested as a prophylactic and anti-relapse treatment with encouraging results. 4,7,8 So far, the potential of tafenoquine as a blood schizontocide for the treatment of multidrug-resistant forms of falciparum malaria has not been methodically explored. The results of studies in animal models and of an in vitro screening investigation of 13 different 8-aminoquinolines showed that tafenoquine has a blood schizontocidal activity that is within a therapeutically achievable concentration range.…”

Section: Introductionmentioning

confidence: 99%

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

Ramharter¹,

Noedl²,

Thimasarn³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC 50 , and 1,414 nmol/L for the EC 90 . Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC 50 , but not at the EC 90 . The EC 50 and EC 90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

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Section: Introductionmentioning

confidence: 99%

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

Ramharter¹,

Noedl²,

Thimasarn³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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“…T he 8-aminoquinoline class of antimalarial compounds is the only molecular scaffold with proven efficacy against relapsing strains of malaria (1)(2)(3)(4)(5). Currently, the only FDA-approved drug from this class that is available for clinical use is primaquine.…”

mentioning

confidence: 99%

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Vuong

Xie

Potter

et al. 2015

Antimicrob Agents Chemother

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dCytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYP mouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.T he 8-aminoquinoline class of antimalarial compounds is the only molecular scaffold with proven efficacy against relapsing strains of malaria (1-5). Currently, the only FDA-approved drug from this class that is available for clinical use is primaquine. Primaquine has been utilized for over 6 decades in treating malaria (6). Despite the long history of primaquine therapy for malaria treatment, primaquine has several disadvantages, including the hemolytic toxicity associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency; its relatively short elimination half-life in humans, which requires daily administration; and the potential requirement for cytochrome P450 (CYP) 2D6-mediated activation for radical curative activity (7-11). The 8-aminoquinoline molecule tafenoquine, currently under late-stage clinical development, has a significantly longer elimination half-life than primaquine (12-16) and has single-dose radical curative activity in humans (3). Tafenoquine is also being developed as a chemoprophylactic agent and has demonstrated efficacy against Plasmodium vivax and Plasmodium falciparum (17)(18)(19)(20)(21). Despite the pharmacological advantages of tafenoquine over primaquine, both molecules seem to have the same pharmacogenomic liability of CYP 2D6-mediated activation for liver-stage antimalarial activity (7,10,22,23) and are not free of hemolytic liability in G6PD def...

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“…A related compound, pyronaridine, was developed in China and is now undergoing extensive clinical trials in other areas (Ringwald et al, 1996). An 8-aminoquinoline, tafenoquine, offers improved activity against hepatic-stage parasites over that of the parent compound, primaquine (Walsh et al, 1999), and is effective for antimalarial chemoprophylaxis (Lell et al, 2000). Since halofantrine use is limited by toxicity, the analog lumefantrine was developed and is now a component of the new combination co-artemether (artemether/lumefantrine; van Vugt et al, 2000).…”

Section: Development Of Analogs Of Existing Agentsmentioning

confidence: 99%

Antimalarial drug discovery: old and new approaches

Rosenthal

2003

Journal of Experimental Biology

189

122

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SUMMARY New drugs against malaria are greatly needed. Many approaches to antimalarial drug discovery are available. These approaches must take into account specific concerns, in particular the requirement for very inexpensive and simple to use new therapies and the need to limit the cost of drug discovery. Among important efforts that are currently ongoing are the optimization of therapy with available drugs, including the use of combination therapy, the development of analogs of existing agents, the discovery of natural products, the use of compounds that were originally developed against other diseases, the evaluation of drug resistance reversers, and the consideration of new chemotherapeutic targets. The last category benefits from recent advances in malaria research technologies and genomics and is most likely to identify new classes of drugs. A number of new antimalarial therapies will likely be needed over the coming years, so it is important to pursue multiple strategies for drug discovery.

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Randomized Dose‐Ranging Study of the Safety and Efficacy of WR 238605 (Tafenoquine) in the Prevention of Relapse ofPlasmodium vivaxMalaria in Thailand

Cited by 89 publications

References 15 publications

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Antimalarial drug discovery: old and new approaches

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