Review: Improving the Therapeutic Index of 8-Aminoquinolines by the Use of Drug Combinations: Review of the Literature and Proposal for Future Investigations

Myint, H.; Berman, Jonathan; Walker, Larry; Pybus, Brandon; Meléndez, Víctor; Baird, J. Kevin; Ohrt, Colin

doi:10.4269/ajtmh.2011.11-0498

Cited by 27 publications

(27 citation statements)

References 23 publications

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“…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)(8)(9)(10)(11). The 8-aminoquinoline molecule tafenoquine, currently under late-stage clinical development, has a significantly longer elimination half-life than primaquine (12)(13)(14)(15)(16) and has single-dose radical curative activity in humans (3).…”

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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mentioning

confidence: 99%

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Vuong

Xie

Potter

et al. 2015

Antimicrob Agents Chemother

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“…Red cell oxidative stress with manifestations ranging from methemoglobinemia (1) to frank life-threatening hemolysis (2) in patients with glucose-6-phosphate dehydrogenase (G6PD)-deficient red cells poses an important safety concern (3). The metabolic activation required for 8-aminoquinoline antimalarial activity is complex and has proven challenging to study due to the reactive, transient nature and low quantities of many of the potentially toxic and efficacious metabolites (4).…”

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confidence: 99%

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Saunders

Vanachayangkul

Im-Erbsin

et al. 2014

Antimicrob Agents Chemother

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e Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (؊)-PQ enantiomer had higher clearance and apparent volume of distribution than did (؉)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (؉)-PQ greater than that seen for (؊)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (؊)-PQ at 4.5 mg/ kg. (؊)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (؉)-PQ at 0.6 mg/kg/day relapsed. While (؊)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (؉) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.

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“…Structure activity relationships indicate that toxicity is difficult to separate from Plasmodium activity. However in a review of the older literature administration of quinine with primaquine increased activity and did not change the toxicity of primaquine [63]. The hypothesis is that these quinolines compete for cytochrome P450 interaction.…”

Section: Primaquine–an 8-aminoquinolinementioning

confidence: 99%

Plasmodium Drug Targets Outside the Genetic Control of the Parasite

Sullivan¹

2013

Current Pharmaceutical Design

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Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition.

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Review: Improving the Therapeutic Index of 8-Aminoquinolines by the Use of Drug Combinations: Review of the Literature and Proposal for Future Investigations

Cited by 27 publications

References 23 publications

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Plasmodium Drug Targets Outside the Genetic Control of the Parasite

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