Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds

Marcsisin, Sean R.; Sousa, Jason; Reichard, Gregory A.; Caridha, Diana; Zeng, Qiang; Roncal, Norma; McNulty, R.; Careagabarja, Julio; Sciotti, Richard J.; Bennett, Jason; Zottig, Victor E.; Deye, Gregory J.; Li, Qigui; Read, Lisa; Hickman, Mark; Nanayakkara, N. P. Dhammika; Walker, Larry; Smith, Bryan; Meléndez, Víctor; Pybus, Brandon

doi:10.1186/1475-2875-13-2

Cited by 72 publications

(78 citation statements)

References 33 publications

(42 reference statements)

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“…54 Altogether, these aspects demonstrate the need to go on searching for alternatives to PQ as antirelapse and transmission-blocking antimalarial agents. Most of the PQ "chemical recycling" efforts made throughout the second half of the 20th century have been extensively revised elsewhere; 47,55 the next examples refer to work from 2000 on.…”

Section: Recycling Primaquine: Toward Novel Antimalarial 8-aminoquinomentioning

confidence: 99%

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“Recycling” Classical Drugs for Malaria

et al. 2014

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Section: Recycling Primaquine: Toward Novel Antimalarial 8-aminoquinomentioning

confidence: 99%

“…47 Interestingly, this finding may provide a possible explanation for patients who do not respond to 8-AQ like PQ for treatment of relapsing malaria, as further discussed below.…”

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“Recycling” Classical Drugs for Malaria

et al. 2014

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“…WT mice express CYP 2D22, which is the mouse cytochrome P450 ortholog closest to human CYP 2D6 (27). Tafenoquine is active when tested in a liver-stage malaria model against Plasmodium berghei that utilizes the WT C57BL/6 mouse strain (10,22). The CYP 2D KO strain contains a deletion of the entire CYP 2D gene cassette and therefore cannot express CYP 2D22.…”

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confidence: 99%

“…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 deficiency (24). This recent discovery suggests that the 8-aminoquinoline class of molecules require CYP 2D6 metabolism for efficacy.…”

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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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“…Other drugs with activity against gametocytes are bulaquine, a compound newly registered in India (12), and tafenoquine, which has been in late-phase clinical development for more than a decade (13). Both drugs are 8-aminoquinolines and are likely to share safety and efficacy problems with primaquine in G6PD-deficient individuals and poor metabolizers of CYP2D6, respectively (14). Dihydroartemisinin (DHA), the active metabolite of all artemisinin derivates, has been reported to be active against stage I to III gametocytes (15,16), but it is uncertain whether DHA has clinically relevant activity against late-stage gametocytes (8).…”

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confidence: 99%

Effect of Fluorescent Dyes on In Vitro -Differentiated, Late-Stage Plasmodium falciparum Gametocytes

Gebru

Mordmüller

Held

2014

Antimicrob Agents Chemother

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dPlasmodium falciparum gametocytes are not associated with clinical symptoms, but they are responsible for transmitting the pathogen to mosquitoes. Therefore, gametocytocidal interventions are important for malaria control and resistance containment. Currently available drugs and vaccines are not well suited for that purpose. Several dyes have potent antimicrobial activity, but their use against gametocytes has not been investigated systematically. The gametocytocidal activity of nine synthetic dyes and four control compounds was tested against stage V gametocytes of the laboratory strain 3D7 and three clinical isolates of P. falciparum with a bioluminescence assay. Five of the fluorescent dyes had submicromolar 50% inhibitory concentration (IC 50 ) values against mature gametocytes. Three mitochondrial dyes, MitoRed, dihexyloxacarbocyanine iodide (DiOC6), and rhodamine B, were highly active (IC 50 s < 200 nM). MitoRed showed the highest activity against gametocytes, with IC 50 s of 70 nM against 3D7 and 120 to 210 nM against clinical isolates. All compounds were more active against the laboratory strain 3D7 than against clinical isolates. In particular, the endoperoxides artesunate and dihydroartemisinin showed a 10-fold higher activity against 3D7 than against clinical isolates. In contrast to all clinically used antimalarials, several fluorescent dyes had surprisingly high in vitro activity against late-stage gametocytes. Since they also act against asexual blood stages, they shall be considered starting points for the development of new antimalarial lead compounds.

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Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds

Cited by 72 publications

References 33 publications

“Recycling” Classical Drugs for Malaria

“Recycling” Classical Drugs for Malaria

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Effect of Fluorescent Dyes on In Vitro -Differentiated, Late-Stage Plasmodium falciparum Gametocytes

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