Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study

Llanos-Cuentas, Alejandro; Lacerda, Marcus Vinícius Guimarães; Rueangweerayut, Ronnatrai; Krudsood, Srivicha; Gupta, Sandeep K.; Kochar, Sanjay Kumar; Arthur, Preetam; Chuenchom, Nuttagarn; Möhrle, Jörg J.; Duparc, Stephan; Ugwuegbulam, Cletus O; Kleim, Jörg‐Peter; Carter, Nick; Green, Justin A.; Kellam, Lynda

doi:10.1016/s0140-6736(13)62568-4

Cited by 214 publications

(281 citation statements)

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“…PQ synthetic methods yield a racemic mixture of these two enantiomers; when PQ was developed, enantiomeric separation of racemates was not available, and single enantiomers of racemic drugs were not the norm in drug development. Later, when the next generation of 8-AQs, namely, bulaquine (Rajgor et al, 2003;Krudsood et al, 2006) and tafenoquine (TQ) (Crockett and Kain, 2007;Llanos-Cuentas et al, 2014), were developed, the same side chain was retained. Thus, PQ is still available as the racemate, and TQ is also being developed as a racemate (LlanosCuentas et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

et al. 2015

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Primaquine (PQ), a racemic drug, is the only treatment available for radical cure of relapsing Plasmodium vivax malaria and blocking transmission of P. falciparum malaria. Recent studies have shown differential pharmacologic and toxicologic profiles of individual PQ enantiomers in rodent, dog, and primate animal models. This study was conducted in six healthy adult human volunteers to determine the plasma pharmacokinetic profile of enantiomers of PQ and carboxyprimaquine (cPQ), the major plasma metabolite. The individuals were orally administered PQ diphosphate, equivalent to 45-mg base, 30 minutes after a normal breakfast. Blood samples were collected at different time intervals, and plasma samples were analyzed for enantiomers of PQ and cPQ. Plasma PQ concentrations were low and variable for both parent enantiomers and peaked around 2-4 hours. Peak (2)-(R)-PQ concentrations ranged from 121 ng/ml to 221 ng/ml, and peak (+)-(S)-PQ concentrations ranged from 168 ng/ml to 299 ng/ml. The cPQ concentrations were much higher and were surprisingly consistent from subject to subject. Essentially all the cPQ detected in plasma was (2)-cPQ. The peak concentrations of (2)-cPQ were observed at 8 hours (range: 1104-1756 ng/ml); however, very high concentrations were sustained through 24 hours. (+)-cPQ was two orders of magnitude lower than (2)-cPQ, and in a few subjects it was detected but only under the limit of quantification. In vitro studies with primary human hepatocytes also suggested more rapid metabolism of (2)-PQ compared with (+)-PQ. The results suggest more rapid metabolism of (2)-PQ to (2) cPQ compared with (+)-PQ. Alternatively, (+)-PQ or (+)-cPQ could be rapidly converted to another metabolite(s) or distributed to tissues. This is the first clinical report on enantioselective pharmacokinetic profiles of PQ and cPQ and supports further clinical evaluation of individual PQ enantiomers.

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Section: Introductionmentioning

confidence: 99%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

et al. 2015

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“…It is greatly hoped that future medications for malaria chemoprophylaxis provide a substantial improvement over current medications and the inevitable problems that arise when introducing a new medication for malaria can be successfully managed. 42 …”

Section: Resultsmentioning

confidence: 99%

Historical Review: Problematic Malaria Prophylaxis with Quinine

Shanks

2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. Quinine, a bitter-tasting, short-acting alkaloid drug extracted from cinchona bark, was the first drug used widely for malaria chemoprophylaxis from the 19th century. Compliance was difficult to enforce even in organized groups such as the military, and its prophylaxis potential was often questioned. Severe adverse events such as blackwater fever occurred rarely, but its relationship to quinine remains uncertain. Quinine prophylaxis was often counterproductive from a public health viewpoint as it left large numbers of persons with suppressed infections producing gametocytes infective for mosquitoes. Quinine was supplied by the first global pharmaceutical cartel which discouraged competition resulting in a near monopoly of cinchona plantations on the island of Java which were closed to Allied use when the Japanese Imperial Army captured Indonesia in 1942. The problems with quinine as a chemoprophylactic drug illustrate the difficulties with medications used for prevention and the acute need for improved compounds.

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“…It can achieve radical cure with a single dose, eliminating the issues associated with poor patient adherence to a 14 day primaquine regimen [54,55,56]. While one study showed its haemolytic potential to be similar to 14 day primaquine in heterozygous females, the drug has an increased risk of a prolonged haemolysis due to its longer half-life.…”

Section: Screening For G6pd Deficiency and Future Options For Radicalmentioning

confidence: 99%

“…While one study showed its haemolytic potential to be similar to 14 day primaquine in heterozygous females, the drug has an increased risk of a prolonged haemolysis due to its longer half-life. Accordingly, the prescription of tafenoquine will demand a quantitative test to screen for G6PD deficiency to rule out patients with an enzyme activity less than 70% [54].…”

Section: Screening For G6pd Deficiency and Future Options For Radicalmentioning

confidence: 99%

The Economics of Vivax Malaria Treatment

Devine¹

2018

Preprint

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The control and eventual elimination of malaria will require widescale adoption of strategies to ensure early diagnosis and highly effective treatment of infected individuals. In Plasmodium vivax, multiple relapse episodes can only be averted by treating the dormant liver stage of the parasite life cycle -a strategy known as radical cure. This thesis aims to investigate key factors determining treatment-seeking behaviour and costs associated with vivax malaria, how these influence healthcare decisions, the cost-effectiveness of screening tests and treatments for radical cure, and the cost-benefit implications of their global implementation.Treatment-seeking behaviour, assessed in Papua, Indonesia, demonstrated that household costs per person seeking treatment for vivax malaria were similar to those for falciparum malaria. Switching from ineffective to effective malaria treatment in the public sector improved the behaviour of patients and both public and private healthcare providers. Diagnostic strategies were investigated on the Thai-Myanmar border, where screening for glucose-6-phosphate-dehydrogenase (G6PD) deficiency prior to radical cure reduced the disease burden while being a cost-effective option for healthcare providers that do not use radical cure and a potentially cost-saving alternative where primaquine is prescribed without screening. The costs of implementing G6PD screening were collected in three countries, and highlighted that RDTs consistently reduced costs as compared to the widely-used fluorescent spot test. Across four countries, the indirect cost due to lost productivity was the largest cost component for households of patients with vivax malaria. After combining provider and patient costs with case estimates, the global economic burden of vivax malaria was estimated to be US$330 million per year. Adopting a policy of screening for G6PD deficiency with delivery of highly effective radical cure was projected to save US$45 million.P. vivax malaria causes a large economic burden that can be reduced substantially by delivering safe and effective radical cure.iii iv

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Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study

Cited by 214 publications

References 20 publications

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Historical Review: Problematic Malaria Prophylaxis with Quinine

The Economics of Vivax Malaria Treatment

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