Compliance with 14-day primaquine therapy for radical cure of vivax malaria—a randomized placebo-controlled trial comparing unsupervised with supervised treatment

Leslie, Toby; Rab, Mohammad Abdur; Ahmadzai, Hayat; Durrani, Naeem; Fayaz, Mohammad; Kolaczinski, Jan; Rowland, Mark

doi:10.1016/s0035-9203(03)00041-5

Cited by 62 publications

(65 citation statements)

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“…prolonged treatment courses are associated with poor compliance (27,28). Since the total dose of, rather than duration of exposure to, PMQ determines the efficacy of radical cure (2, 29, 30), abbreviated treatment courses have been developed.…”

Section: Figmentioning

confidence: 99%

Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

Moore

Salman

Benjamin

et al. 2014

Antimicrob Agents Chemother

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f Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/ h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (C max ) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher C max for PMQ and CPMQ, respectively. All predicted median C max concentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group. P rimaquine (PMQ) is an 8-aminoquinoline drug used for primary (causal) and terminal malaria prophylaxis, radical cure of Plasmodium vivax and P. ovale, and as a gametocytocidal agent in P. falciparum infections (1-4). It remains the only FDA-approved drug for elimination of liver stages (hypnozoites and schizonts) of P. vivax and P. ovale (2,4,5). In many non-African tropical countries, such as Papua New Guinea (PNG), there is hyperendemic transmission of P. vivax (5-7). Children carry the burden of repeated P. vivax infections in this geoepidemiologic setting (5,8,9). Therefore, a safe and effective radical cure would benefit personal well-being, growth, and development and lessen the economic impact of the infection on the community (10).Primaquine is conventionally administered as a 14-day course for terminal prophylaxis and radical cure (2), but this regimen can be problematic due to poor compliance (1, 5). An abbreviated regimen would have advantages (11, 12) as long as it was safe and well tolerated. Pharmacokinetic studies of PMQ to date have been conducted only in adults (6). As the pharmacokinetic and pharmacodynamic profiles of antimalarial drugs can differ between adults and children (13), there is a need for a study of PMQ disposition in the pediatric age grou...

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Section: Figmentioning

confidence: 99%

Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

Moore

Salman

Benjamin

et al. 2014

Antimicrob Agents Chemother

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“…Park and Kang (162) measured only a 32% effectiveness of postexposure presumptive therapy with the 15-mg daily (14-day) regimen for tens of thousands of soldiers from the Republic of Korea. The 30-mg daily (14-day) regimen achieved 94% efficacy in the northwestern frontier of Pakistan (135), whereas a supervised regimen of 15 mg daily achieved only 48% efficacy in the first 3 months in the same region (133). Another study in the same region recorded a 35% efficacy for that regimen (187 Risk of reinfection may confound these studies from India, Pakistan, and Afghanistan with long-term follow-up (9 to 12 months).…”

Section: Distributionmentioning

confidence: 99%

Resistance to Therapies for Infection by Plasmodium vivax

2009

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SUMMARY The gravity of the threat posed by vivax malaria to public health has been poorly appreciated. The widely held misperception of Plasmodium vivax as being relatively infrequent, benign, and easily treated explains its nearly complete neglect across the range of biological and clinical research. Recent evidence suggests a far higher and more-severe disease burden imposed by increasingly drug-resistant parasites. The two frontline therapies against vivax malaria, chloroquine and primaquine, may be failing. Despite 60 years of nearly continuous use of these drugs, their respective mechanisms of activity, resistance, and toxicity remain unknown. Although standardized means of assessing therapeutic efficacy against blood and liver stages have not been developed, this review examines the provisional in vivo, ex vivo, and animal model systems for doing so. The rationale, design, and interpretation of clinical trials of therapies for vivax malaria are discussed in the context of the nuance and ambiguity imposed by the hypnozoite. Fielding new drug therapies against real-world vivax malaria may require a reworking of the strategic framework of drug development, namely, the conception, testing, and evaluation of sets of drugs designed for the cure of both blood and liver asexual stages as well as the sexual blood stages within a single therapeutic regimen.

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“…One study showed comparable efficacy of the 14-day course following strong health messaging and clear instructions for completion of the course in Afghan refugees in Pakistan. 111 Short-course, high-dose regimens have potential to increase patient adherence, and thus effectiveness, 112 but appropriately powered prospective multicentered randomized controlled trials are needed to assess the tolerability, safety, efficacy, and effectiveness of such alternative radical curative regimens against current best practice.…”

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confidence: 99%